June 25, 2015

Part II: Pharmacology of Conventional

Chemotherapeutics

1
Pharmacology of Conventional Chemotherapeutics
Part II: LECTURE OVERVIEW
The Big Picture:
Classification of antineoplastic agents
Mechanisms of Action of Anticancer Drugs:
Sites of Action
Selectivity
Cell Cycle Non-Specific vs. Cell Cycle-Specific Agents
Pharmacology of agents:
DNA Alkylating Agents
Platinum Compounds
Antitumor Antibiotics
Topoisomerase Inhibitors
Antimetabolites
Mitotic Inhibitors

2
 Part II Conventional Chemotherapeutic
Drug Classes

Learning Objectives for Each Drug Class:

!
Discuss the sites of action of antineoplastic drugs
Identify which drugs/groups are CCS or CCNS
(generic names only. If a brand name
Know the drug names within each class is used, generic will be given along
with it)
Compare and contrast the pharmacology of each class (or
drugs within each class) of chemotherapeutic agents:
Mechanism of action
Pharmacokinetics
Toxicities common and unique & mechanisms of toxicities
Mechanisms of resistance

3

The Big Picture: Chemotherapeutic Agents

Drugs that act on DNA or Mitotic Spindle or Cell

Signaling
Cell-cycle specific or cell-cycle non-specific
Each have different mechanisms of action

DNA Alkylating Agents

Kill cancer cells but also normal cells
Platinum Compounds
Antitumor Antibiotics Cytotoxic agents:
Topoisomerase Inhibitors Conventional chemotherapy
Discovered a long time ago and still used today in tx
Antimetabolites
of cancer
Mitotic Inhibitors
!
Targeted Therapies (newer class of drugs)
Difference: chemotherapy is targeted to dividing cells. All cells that divide need the microtubules and
this causes significant side effects (e.g. nerve fibers and thats why neuropathy occurs with these drugs)
Targeted agents have a much narrower target. Oncogenes are not critical part of all cells 4
 The Big Picture: Chemotherapeutic Agents &
Mechanism Based Classification target a protein, enzyme thats responsible
.
for proliferation

Cytotoxic Agents Targeted Therapies

Affect all actively dividing Affect the molecular
cells in the body - both circuitry responsible for
cancerous and healthy. Some dysregulated proliferation
affect resting cells

alter DNA in M phase (mitosis)

Hormones and Receptors and
Action on DNA Action on
hormone intracellular
! mitotic spindle
modulators signaling
! ! ! !
! ! ! !
! ! !
Alkylating agents
Platinum compounds
Antitumor
antibiotics Microtubule Hormones Growth signal
Topoisomerase inhibitors Modulators of pathway
inhibitors hormone inhibitors
Antimetabolites release and Angiogenesis
action inhibitors 5
A.Gardner, 2009
 The Big Picture: Chemotherapeutic Agents &
Put all the drugs in
Mechanism Based Classification
this chart to study

Cytotoxic agents Targeted therapies

Action on DNA Action on Hormonal Agents Targeted Therapies

Mitotic spindle

Microtubule Inhibitors:
Vincristine
Damage DNA Inhibit synthesis

Agonists: Antagonists:
Prednisone Tamoxifen
Letrozole
alkylates DNA Growth signal pathways:
Alkylation: Antimetabolites:
Cyclophosphamide Imatinib
5Fluorouracil Cetuximab
Methotrexate
Free radical
Formation
Drugs fit Angiogenesis
/Intercalation:
into the DNA Doxorubicin Inhibitors:
helix and Bevacizumab
distort it Topoisomerase Thalidomide
Inhibitors: very imp in replication of DNA (prevent development
= intercalation
Irinotecan of blood supply of the
tumor)
 The Big Picture: Mechanisms of Action
of Chemotherapeutic Agents

damage
DNA

imp for pulling

the chromosomes
DNA is converted to mRNA which apart during mitosis
then produces protein. These
prevent protein synthesis -> G1
and G2 has a lot of growth and youre
inhibiting that
induces differentiation in cells - prevents a cancer cell from progressing
to the de-differentiate phase -> prevent cancer from getting aggressive
 Mechanisms of Action of
Chemotherapeutic Agents

Four major cellular

processes are targets
for conventional
chemotherapy
1. DNA Synthesis
2. RNA Synthesis
3. Protein Synthesis
4. Cell Division

E = enzyme
8
Mechanisms of Action of Chemotherapeutic
Agents: Action on DNA
prevents both purine and pyrimidine synthesis

prevents purine synthesis

Majority of the conventional

chemotherapeutic drugs act on the
DNA: damage it or prevent synthesis

ImageMD

The majority of anticancer drugs (cytotoxic agents) act on DNA by either

damaging DNA or inhibiting its synthesis and function within the cancer
cell
 Mechanisms of Action of Chemotherapeutic
Agents: Action on Cell Cycle
Antibiotics + Topoisomerase inhibitors

! Antimetabolites
Cytotoxic agents that act on DNA
can be cell cycle specific or S
(2-6h)
nonspecific G2
Vinca alkaloids
Cell-cycle-specific (CCS) drugs (2-32h)
affect cells at specific phase Mitotic
inhibitors
Effective for high growth M
(0.5-2h)
fraction tumor cells Taxoids
Cell cycle-nonspecific drugs
(CCNS) modify cells at any phase
Effective for low growth
fraction tumor cells
Note, other agents that do not
act on DNA can be cell cycle Alkylating agents, platinum compounds, cell signaling inhibitors
e.g. mitotiic inhibitors that act on M phase
specific G1
CCS: The focus is at the S phase of the cell cycle -> disrupt (2-h)
DNA synthesis -> cant duplicate the cells anymore.
Others target S, G2, G1 phases: specific for cells with high growth fraction e.g. leukemia
CCNS: target at any phase e.g. akylating agents, platinum compounds. Draw cells G0
from the G0 phase and take them into cell cycle. They modify the DNA and when the DNA tries to replicate, it cant b/c
so badly damaged. So thats why they are called CCNS b/c having this effect on G1 and S phase. 10
Good for low growth fraction tumor cells.
Cytotoxic agents only affect actively dividing cancerous cells in the body. False

There are non-cell cycle specific agents as well. So therefore these agents are going to operate in the G0 phase ->
draw cells out and put them into cell cycle. So theyre having an effect in a phase which is not part of the cell cycle.
G0 phase is the resting phase -> not proliferating
Chemotherapeutic Agents that Damage DNA

Cytotoxic Action Alkylating agents

on DNA Platinum compounds
! Antitumor antibiotics
! Topoisomerase Inhibitors
! !

DNA Alkylating Agents & Platinum

compounds: Damage DNA and damage it in a pretty bad way

All form DNA adducts -chemicals

form a covalent bond with the DNA - damage it b/c those
shouldnt be attached to the DNA

In general are Cell-Cycle Non-Specific Agents

Target cells in G0 and draw them out. When they go into S phase, b/c the DNA
is so badly damaged, cant be synthesized

11
Relating Chemotherapeutic Agents to Cell Cycle
Antibiotics + Topoisomerase
inhibitors
Antimetabolites
S
(2-6h)
G2
(2-32h)
Vinca alkaloids
M
(0.5-2h) Mitotic inhibitors
Taxoids

Alkylating agents, platinum compounds, cell signaling inhibitors

G1
(2-h)

G0
12
 DNA Alkylating Agents & Platinum
compounds:
DNA Alkylating Agents:
Nitrogen Mustards: The first chemotherapeutic agents.
Including: Mechlorethamine, Chlorambucil, Melphalan,
Cyclophosphamide, Ifosfamide
Nitrosureas:
Including: Carmustine and Lomustine, Streptozocin

Mechlorethamine Chlorambucil Melphalan Cyclophosphamide

Ifosfamide Carmustine Lomustine Streptozocin 13

Lances Story:

Lance Armstrong, the professional road racing cyclist, was 25 y/o when he was diagnosed with Stage
III testicular cancer. The cancer had metastasized to his abdomen, lungs and brain. He was
treated at Indian medical center. He underwent two surgeries to remove the cancerous lesions
in his testicles and brain. His chemotherapy tx consisted of one 3-week cycle of BEP (bleomycin,
etoposide, and Platinol/Cisplatin) chemotherapy, followed by three cycles of VIP chemotherapy
(Vinblastine, Ifosfamide, and Platinol/Cisplatin)

Ifosfamide used b/c it can draw the cancer cells out into the cell cycle.
 DNA Alkylating Agents: General Mechanism
of Action
Prodrugs = have to be converted into
active, biological form thatll target cancer cells

Prodrugs that are

converted, in vivo, to active
metabolites by:
A) Spontaneous conversion
to active metabolites in
body fluids to- the active form:
Mechlorethamine,
carmustine, lomustine,
streptozocin
OR
B) Enzymatic conversion (Cytotoxic form)
Cyclophosphamide
(CYP2B6) and
Ifosfamide (CYP3A4)
These require the CYP enzymes to be
active. These enzymes are found in the
liver and all throughout the body. Cyclo 14
can be given PO or IV and Ifos IV only. Lippincotts Illustrated Reviews: Pharmacology, 2nd Ed
Enzymatic conversion
of cyclophosphamide

*** Know the metabolites that are causing DNA damage and
the ones that are causing damage to normal cells (cytotoxic)

Metabolism/Excretion:
Pro-drug activated by
P450 System to
cytotoxic compounds
Metabolites excreted in Urine

Cyclophosphamide is a prodrug (inactive). CYP2D6 will metabolize

it to aldophosphamide which is active and then goes further
Alkylating
conversion to two important metabolites:
agent
phosphomide mustard: this is the one that damages the DNA
acrolein: causes the toxic side effect

Ifosfamide: metabolized by CYP3A4 and forms two metabolites

Active alkylating agent is isophosphoramide 15
Cytotoxic metabolite = chloracetaldehyde Golan et al
15
 DNA Alkylating Agents: General
**Know the general MOA

Mechanism of Action
and also which DNA sites
are prone to alkylation.
undergo modification to a
molec thats highly electrophilic
and seeks nucleophiles in the DNA
Conversion:
Active alkylating form of drug
(highly electrophilic)+ leaving
group
Cytotoxicity is induced by
transfer of alkyl groups to DNA DNA Adduct
(and other cellular
macromolecules).
Covalent bonds with alkyl group
of the drug & nucleophilic group purine of DNA Electrophile covalently
of DNA. binds the DNA.

DNA sites that are prone to Cross-linked DNA

purine on DNA purine on DNA
alkylation - N7-Guanine, N1 & drug
N3-adenine; N3-cytosine; others
Majority of alkylating agents are
b/c alkylate two sets of nucleotides
bi-functional alkylators. Now have purine or a pyrimidine with huge groups 16
bound
Most modify at two groups of DNA so synthesis of DNA is disrupted
 DNA Alkylating Agents: General Mechanism of Action

Guanine alkylation has several consequences

DNA Damage: Problem is that dual alkylators are much much more
aggressive at damaging the DNA.
Monofunctional alkylation (chlorambucil)
Agents that are only mono-functional (adduct to one
Guanine excision from DNA
nucleotide), they will still be exised and if bad enough will
Abnormal base-pairing with T be sent to apoptosis. Sometimes can overcome
Dual alkylations this damage. Repair DNA and abnormal pairing of DNA ->
Cross-link DNA strands: causes mutation and passed on through cells -> secondary
Base excision cancers can develop
Or prevent repair and strand
separation, thus interfering with
replication and transcription
(both require DNA strand separation).

Drug

Binds to two nucleotides so when DNA tries to replicate, there is a problem.

p53 tries to repair it and they cut out the nucleotides that have these big
modifications on them. When you do this several times (cutting out several pieces of
damaged DNA), its very difficult for the DNA to be repaired -> signal goes out to
17
send in apoptosis b/c damage is so bad and cant be repaired -> cancer cell dies and doesnt
replicate anymore.
 DNA Alkylating Agents: General Mechanism of Action

Guanine alkylation has several consequences

APOPTOSIS - the p53 gene senses DNA damage

and initiates apoptosis in response to DNA
alkylation
Outcome: DNA synthesis and cell division
disrupted; cell death
Note: Process leads to mutations in DNA
Abnormal base pairings Text

Risk of secondary cancers

18
DNA Alkylating Agents:Pharmacokinetics

Mechlorethamine
Rapidly & spontaneously converted
to its alkylating intermediate (doesnt need CYP conversion)
Powerful vesicant, so it is only
administered i.v.
Unstable in aqueous solutions -> protocols when to
administer this drug
Rapid metabolism

Mechlorethamine
Lippincotts Illustrated Reviews: Pharmacology
5th Ed
19
DNA Alkylating Agents:Pharmacokinetics
Drug crosses the
blood-brain barrier

Cyclophosphamide & Ifosfamide -

prodrugs - hepatic P450 enzymescan cross BBB Oral route
Cyclophosphamide (CYP2B6) PO, IV
Ifosfamide (CYP3A4) IV only
Active metabolites: phosphoramide
(alkylating)mustard and acrolein (damages normal cells)

*** Remember active metabolites of cyclophosphamide and

ifosfamide

cyclophosphamide

Lippincotts Illustrated Reviews: Pharmacology

5th Ed

20
DNA Alkylating Agents:Pharmacokinetics
Drug crosses the
blood-brain barrier

Lomustine

Carmustine/Lomustine

Lippincotts Illustrated Reviews: Pharmacology

5th Ed
Carmustine, Lomustine
New tx for brain cancer, take these drugs and implant them
Lipophilic agents - distribute to fatty
into a wafer. Wafers are loaded with the drug carmustine. The
tissues & CNS (can cross BBB)
surgeon implants them into the brain cavity. These disks slowly
release the drug into the area where the brain cancer is. Brain tumors
Carmustine is unstable in aqueous 21
solution
 DNA Alkylating Agents:Toxicity
All DNA Alkylating Agents cause:
! b/c bone-marrow cells have a high growth fraction and these drugs target the cells with high growth fraction

Bone-marrow
(WBC low)
toxicity = Myelosupression:
leukopenia and thrombocytopenia (mouth ulcers)
(platelet low)

Mucosal toxicity = Oral ulceration, intestinal

(starts in mouth and goes all the way through the gut)
epithelium sloughing
CNS toxicity = Nausea, vomiting (stop having period and can have
early-onset menopause)
Reproduction disorders = Amenorrhea,
azoospermia (lack of sperm)
Immunosuppression-(e.g. very susceptible to getting infections
viral, fungal infections)

Alopecia = loss of hair

b/c hair follicles have a high growth fraction

22
DNA Alkylating Agents:SpecificToxicities

Specific DNA Alkylating Agent Toxicities:

! b/c its a monofunctional

Chlorambucil: alkylating agent that can cause

mutations in DNA thats passed on

Sterility, secondary acute leukemia generations -> secondary leukemia

Carmustine, Lomustine:
Myelosuppression - delayed and prolonged
low platelets for a very long time -> affects clotting ->
- thrombocytopenia bleed easily and prolonged bleeding
Streptozotocin:
Diabetogenic (can cause diabetes b/c destroys beta cells in the pancreas that produce
the insulin)
Mechlorethamine:
Extravasation Causes skin damage like blistering. Causes a lot of damage at the site
of administration

23
DNA Alkylating Agents: b/c of acrolein:

Specific Toxicities when it gets in to the bladder, causes damage to the lining
of the bladder. Immediately put in the catheter so it drains
b/c the longer the urine with acrolein is in the bladder, the
more damage there will be.

Cyclophosphamide, Ifosfamide:
Hemorrhagic cystitis
Dose-limiting toxicities
Acrolein = toxic metabolite
Antidote = Fluid + MESNA (sodium 2-mercaptoethane
sulfonate) - MESNA detoxifies acrolein
Ifosfamide:
Neurotoxicity due to the toxic metabolite chloracetaldehyde

(problems with walking)

Seizures, ataxia, altered mental status, coma
Chloracetaldehyde= toxic metabolite
Can treat with methylene blue to tx the toxic effects of ifosfamide
 Summary of Toxicities of DNA Alkylating Agents
**Study guide

Drug Class Toxicities Specific Toxicities

Nitrogen Mustards: Bone-marrow toxicity
(myelosupression,
Cyclophosphamide hemorrhagic cystitis
leukopenia,
Ifosfamide thrombocytopenia), hemorrhagic cystitis,
Mucosal toxicity (oral neurotoxicity
ulceration, intestinal
Mechlorethamine epithelium sloughing, CNS extravasation
Chlorambucil toxicity (nausea & sterility, secondary acute
vomiting), Reproductive leukemia
disorders (amenorrhea,
Nitrosureas: azoospermia),
Carmustine Immunosuppression, and myelosuppression
alopecia. (thrombocytopenia) delayed &
prolonged
Lomustine myelosuppression
(thrombocytopenia) delayed &
prolonged

Streptozocin altered glucose metabolism

Camp et al., 2007; Polovich et al., 2009; Wilkes & Barton-Burke, 2008;Oncology Nursing Society.
25
 Mechanisms of Resistance to Alkylating
Agents
Stop responding to tx, tumor might
increase in size
Resistance can occur by many ways

Decreased uptake permeability

Increased activity of DNA repairs enzymes.
Increased rates of metabolism to inactive
form of drug example,
cyclophosphamide
Increased production of nucleophiles such
as glutathione (-SH group)
Increased efflux of drug
26
***Do not need to know

DNA Alkylating Agents: Clinical Use

Nitrogen mustards clinical spectrum of use is broad:
Cyclophosphamide non-Hodgkins lymphoma, lymphoid
malignancies, breast and ovarian cancers, solid tumors in
children
Melphalan multiple myeloma
Chlorambucil - Chronic Lymphocytic Leukemia (CLL)
Mechlorethamine - palliative treatment of Hodgkin's
disease (Stages III and IV), lymphosarcoma, CLL
Nitrosureas:
Carmustine - malignant gliomas, glioblastoma multiforme
Streptozocin pancreatic islet cell carcinoma, malignant
carcinoid tumors

27
Which of the follow drugs is most likely to cause hemorrhagic cystitis?
A. mechlorethamine
B. cyclophosphamide
C. carmustine
D. Lomustine
Correct: B

All alkylating agents undergo spontaneous conversion to the active cytotoxic metabolite.
False

Select the correct statement regarding alkylating agents:

a) only administered by IV infusion
b) all form DNA adducts
c) all are bifunctional DNA cross linkers
d) metabolites are cleared by the liver
Correct: B
Some metabolites are cleared by the urine

DNA alkylating agents promote?

a) cell growth
b) apoptosis
c) cell survival and proliferation
d) none of the above
Correct: apoptosis
June 30, 2015

Platinum Compounds
Form DNA adducts but they dont alkylate, they form different types of modifications to the cancer cell.

Carboplatin All these damage DNA. They have a platinum molec at the center of
their design -> makes them very interesting when it comes to damaging
Cisplatin DNA

Oxaliplatin

28
 Relating Chemotherapeutic Agents to Cell
Cycle
Platinum compounds are non-cell cycle Antibiotics + Topoisomerase
specific agents. They target cells in
G0 (resting) and in the S phase.
inhibitors
Antimetabolites
S
(2-6h)
G2
(2-32h)
Vinca alkaloids
M
(0.5-2h) Mitotic inhibitors
Taxoids

Alkylating agents, platinum compounds, cell signaling inhibitors

G1
(2-h)

G0
29
 Clinical Application of Drug Therapy:
Lance's story
Lance Armstrong, the professional road racing
cyclist, was 25-years-old when he was diagnosed
with stage III testicular cancer (60%
choriocarcinoma, 40% embryonal and less than 1%
teratoma). The cancer had metastasized to his
abdomen, lungs and brain. He was treated at
Indiana University Medical Center by Drs. Larry
Einhorn and Craig Nichols. He underwent two
surgeries to remove cancerous lesions in his
testicle and brain .His chemotherapy treatment ,
from October to December, consisted of one 3-
week cycle of BEP (Bleomycin, Etoposide and
Platinol /Cisplatin) chemotherapy, followed by http://
three cycles of VIP chemotherapy (Vinblastine, www.teamradioshack.us/
Ifosfamide, and Platinol /Cisplatin). lance-armstrong-profile/
Cisplatin was used in both regimens.
30
http://www.livestrong.org/site/c.khLXK1PxHmF/b.2661053/k.9207/Lances_Story.htm; http://tcrc.acor.org/

Platinum drugs: Mechanism of Action
cancer and normal
Enter cells via active Cu2+ transporter
Chloride, cyclohexane or oxalate ligands of the Pt6+
analogs displaced by water (inside cells) Once inside the cell, converted
to a form that will damage DNA
Yields positively charged, highly reactive molecule
Aquated species results in formation of intrastrand
(primarily) and interstrand (less frequently) crosslinks => DNA
damage
DNA damage
Different leaving groups for the different drugs:
Cl for cisplatin
Cyclohexane for Carboplatin
Oxalate for Oxaloplatin

Cisplatin react with the H2O

inside the cell and removes
the leaving groups and that yields a highly positively charged biological molec. that will
damage the DNA. It looks for the nucleophiles in the DNA. Platinum molec. crosslinks to the
DNA, can crosslink between nucleotide on the same strand or the opposite strand -> 31
DNA damage. DNA is stuck there, cant come apart to synthesize.

Platinum drugs: Mechanism of Action
!
Intrastrand cross-links are
covalent platinum-nitrogen
bonds primarily at N7 of
guanine residues.
Intrastrand G-G Cross-links.
These are very damaging to DNA -> cant synthesize or
!
replicate it. The cancer cell can no longer replicate

DNA cross-linking interferes

with DNA processing and Platinum
function. Complex
!
APOPTOSIS - the p53 gene
senses DNA damage and
initiates apoptosis
Body senses the damaged DNA and sends the cancer
cells in apoptosis.

***Know the differences between alkylating agents and

platinum compounds - both form adducts with DNA but compounds
32
added are different. Golan, Prinicples of Pharmacology, 2 Ed
nd
 Platinum drugs: Pharmacokinetics
Not absorbed orally

No oral bioavailability administered via slow

intravenous infusion
!
When giving by IV infusion, it concentrates in certain organs more than others:
-> useful to txing
High concentrations liver, intestine, testes, testicular cancer
kidneys
!
-> side effects
Excreted by kidneys*
Carbo > Cis and Oxal
70% 40-50% Therapeutic consideration:
Aluminum reacts with and inactivates
cisplatin Rx must not contact needles,
infusion equipment containing Al3+
during its preparation or administration
Al will react with Platinum and decrease the potency
of the drug

33
 Platinum drugs: Toxicity
-> majority of the drug is excreted by the kidney
Nephrotoxicity Cisplatin worse at causing nephrotoxicity than carbo and oxali
Cisplatin >> Carboplatin and Oxaliplatin
damages nerves responsible for hearing -> prolonged
Ototoxicity & neurotoxicity exposure can lead to deafness

Very severe nausea and vomiting g

Ondansetron (5HT3 antagonist) t

Carboplatin:
Less nephrotoxicity, ototoxicity, neurotoxicity and
severe nausea can accumulate in the spine and cause
Hypersensitivity Reaction peripheral neuropathy
Dose-limiting toxicity is myelosuppression
(thrombocytopenia)
Oxaliplatin:
Dose-limiting toxicity is neurotoxicity
(peripheral neuropathy)
Concentrates more in the spine and causes the peripheral neuropathy

*** Know the ADEs and compare the differences between these drugs 34
 Platinum Drug-induced Nephrotoxicity
Associated with higher than normal recommended
doses
Accumulation of cisplatin
causes apoptosis of tubular epithelial cells
Concentrate in the proximal tubules of the kidney and causes cell death of the proximal tubule cells
Nice to know:
Causes a lot of stress by producing free radicals -> apoptosis (triggers death receptor
pathway). These pathways triggered into endoplasmic reticulum result in the
cell death of the proximal tubule cells of the kidney.

Normal Cisplatin-induced
proximal tubules proximal tubular toxicity

Kidney International (2008) 73, 9941007; doi:10.1038/sj.ki.

5002786; published online 13 February 2008
 Therapeutic consideration:
!
1. Treatments
! to prevent renal damage:
Chloride diuresis 1-2 L of normal saline is
administered before treatment with this drug
! through. Giving much more Cl in the water so it stabilizes the drug and the Cl molec dont leave
Flushes the drug
and dont get activated.
Amifostine used to protect the kidney. It is a
thiophosphate that is dephosphorylated by alkaline
phosphatase to a thiol metabolite. The metabolite is
taken into the cell and the increased thiol
concentration acts as a scavenger of Cisplatin
metabolites
2. Kidney function
Creatinine clearance < 60 ml/min needs dosage
adjustment
36
Practical Application - Influence
.
of sodium
chloride
Concentration on Cisplatin Nephrotoxicity
Kidney epithelial cells (LLC-
PK1) were grown
Cells were incubated in
varying amounts of NaCl
with or without cisplatin
Cell survival was then
tested
- Cisplatin
! + Cisplatin
Therapeutic Consideration:
Cl- diuresis
!
Kidney cells grown in a petri dish and looking to see if they
survive in the absence or presence of cisplatin in addition to
varrying levels of sodium chloride mixture.
As you increase the conc. of NaCl, in cells with no Cisplatin ->
theres almost a 100% survival. With Cisplate, if you increase Hanigan M H et al. Am J Physiol Renal Physiol
2005;288:F125-F132
the conc. of NaCl, the cells survive so it does prevent the cell death. 37
2005 by American Physiological Society
Check first clicker: All of the above

Correct statement with cisplatin, carboplatin, oxaliplatin:

1. All are equally nephrotoxic
2. Form metal adducts with DNA
3. Drugs are inactivated by zinc
4. Enter cells primarily by passive diffusion
Correct: 2
 Mechanisms of Resistance to Platinum
Compounds

Decreased copper transporters ->up less of the drug is taken

into the cell

Increased production of nucleophiles such

as glutathione (-SH group) -> scavenges the metabolites of cisplatin
Increased activity of DNA
-> chops out the metal adduct and start proliferating
repair enzymes
Increased efflux of drug

38
 Platinum Drugs: Clinical Use
Generally used against a wide range of slow growing solid
tumors :
Testicular
Ovarian
Bladder
Lung
Breast

http://
www.teamradioshack.us/
lance-armstrong-profile/

39
http://www.livestrong.org/site/c.khLXK1PxHmF/b.2661053/k.9207/Lances_Story.htm; http://tcrc.acor.org/
 Summary of Toxicities of Platinum Drugs
Drug Class Toxicities Specific Toxicities
Platinum Compounds: Nephrotoxicity (Cis>>Car
& Oxa), Ototoxicity,
Cisplatin Neurotoxicity, Severe Renal Damage, Otoxicity.
Carboplatin Nausea & Vomiting. Hypersensitivity Reaction
! Dose limiting:
** Carboplatin has less thrombocytopenia
nephrotoxicity,
Oxaliplatin ototoxicity, neurotoxicity Dose limiting: neurotoxicity
and severe nausea & (peripheral neuropathy)
vomiting.

Camp et al., 2007; Polovich et al., 2009; Wilkes & Barton-Burke, 2008;Oncology Nursing Society.

With chemotherapy, need to know the MOA and ADEs.

40
Summary of Alkylating & Platinum Agents
Alkylating agents have alkyl groups that can form
formed covalent bonds with cell substituents; a
adducts

carbonium ion is the reactive intermediate.

Most alkylating agents have two alkylating groups
and can cross-link two nucleophilic sites such as
the N7 of guanine in DNA. Cross-linking can:
Cause defective replication
Owing to pairing of alkylguanine with thymine, and
then substitution of AT for GC
Leading to excision of guanine and chain breakage
Their principal effect occurs during DNA
synthesis; the resulting DNA damage triggers
apoptosis.
41
 Summary of Alkylating & Platinum
Agents
The main alkylating agents are nitrogen
mustards and nitrosoureas.
Cisplatin causes intrastrand linking in DNA; it
has low myelotoxicity but causes severe nausea
& vomiting and can be nephrotoxic. It has
revolutionized the treatment of germ cell
tumors. such as testicular and ovarian cancers

42
 Part II Conventional
Chemotherapeutic Drug Classes

Learning Objectives for Each Drug Class :

!
Discuss the sites of action of antineoplastic drugs
Identify which drugs/groups are CCS or CCNS
Know the drug names within each class
Compare and contrast the pharmacology of each class (or
drugs within each class) of chemotherapeutic agents:
Mechanism of action
Pharmacokinetics
Toxicities common and unique & mechanisms of toxicities
Mechanisms of resistance

43
Chemotherapeutic Agents that Damage DNA

Cytotoxic Action Alkylating agents

on DNA Platinum compounds
! Antitumor antibiotics
! Topoisomerase inhibitors
!

Antitumor antibiotics:
In general are Cell-Cycle Specific Agents

44
 Relating Chemotherapeutic Agents to Cell Cycle
CCS: G1, S and G2 phase Antibiotics + Topoisomerase
Operate during the S phase of the inhibitors
Antimetabolites
cell cycle
S
(2-6h)
G2
(2-32h)
Vinca alkaloids
M
(0.5-2h) Mitotic inhibitors
Taxoids

Alkylating agents, platinum compounds, cell signaling inhibitors

G1
(2-h)

G0
45

Chemotherapeutic Drugs that Damage DNA

Anthracyclines:
Doxorubicin
Daunorubicin
Idarubicin
Epirubicin
Other Antibiotics:
Bleomycin
Dactinomycin (Actinomycin D)D)

46
Anthracyclines:
Doxorubicin
Daunorubicin
Idrarubicin
Epirubicin

Doxorubicin

47
 3 MOA

Mechanism of Action: Anthracyclines

Intercalates -> form a wedge, insert themselves
into DNA -> warps the DNA and inhibits DNA
synthesis. Also inhibits toposiomerase II. Topo
cuts DNA when its unwinding and that limits the
strain on the DNA. When inhibited, everything
comes together and you get DNA strand breaks
Three major mechanisms:
Intercalation of DNA
Inhibits DNA & RNA Topo
synthesis
Inhibition of
topoisomerase II
DNA strand breaks
Free radical formation
Generate semiquinone Generate free radicals.
Free radicals are very
free radicals and damaging to cells -> can
oxygen free radicals. cause a lot of damage in
Cause DNA strand the cancer cells.
scission, peroxidation Cause problems with the
membrane of the cancer
of membrane lipids, cells. Free radicals
oxidation of purines & chemically modify purines
pyrimidines and pyrimidines 48
Anthracyclines: Pharmacokinetics
Usually administered intravenously (very big molecs.)
Cleared through hepatic metabolism and
biliary excretion
All are converted to an active alcohol
intermediate that has therapeutic activity
(cant be used to tx brain cancers)
They do NOT cross the blood brain barrier
Hepatic dysfunction delays the clearance
of anthracyclines and their metabolites
and increases the toxicity

49
PEGylated liposomal doxorubicin:
Pharmacokinetics Doxirubicin can be given nano-particle delivery as a liposome.
This increases tumor localization and increases half life of the
Doxil / Caelyx drug -> better targeting of the drug to the cancer cell
**Be aware of this formulation
FDA 2005

http://www.doxil.com

Nanoparticle: Dox encapsulated in liposomes

pharmacological activity
plasma half-life
tumor localization
50
 Anthracyclines: Toxicity
Myelosuppression
Alopecia
PEGylated liposomal doxorubicin:
painful
Hand-foot syndrome (swelling, redness, blistering)
Vesicant
- extravasation injuries -> when
you have this blistering at
the site of administration,
it starts to leak into the tissue
nearby and the result is that
it causes necrosis of the
tissue in the surrounding area.
 Anthracyclines: Toxicity
Cardiotoxicity:
Acute and chronicElevation of
cardiomyopathies
ST wave, bundle branch block
(heart muscle and
ACUTE = Abnormal EKG changes: Arrhythmias;
pericardial sac that
covers the heart Pericarditis-myocarditis
Protocols there to not
syndrome
go over a cumulative dose of a certain amount
get inflamed) ->
acute HF CHRONIC = Irreversible, cumulative & dose-dependent
Congestive cardiac failure
Poorly responsive to digitalis

Also, be aware of the total cumulative dose!

Therapeutic consideration:
Pre-treatment with drug requires base-line cardiac performance
Concomitant use of cardioprotective agent
Iron chelator. Iron is part of the mechanism that causes
Dexrazoxane (Zinecard) cardiotoxicity so if you scavenge all that iron, it helps reduce cardiotoxicity
PEGylated liposomal doxorubicin : cardiotoxicity(still some toxicity but less)
!
 Iron creates formation of free radicals -> change the SR in the heart, destroys the membranes of the SR (called
peroxidation) -> causes loss of Ca binding sites -> load of Ca pouring into the heart muscle -> the heart hates too
much Ca (damages the heart) -> excess Ca disrupts the actin-myosin filaments and mitochondrial ATP formation.
Mechanism of Anthracycline-induced Cardiotoxicity
- EF fails to detect subtle changes in the heart related to
the chemotherapeutic agents
iron-catalyzed formation of
- Decrease in left ventricular longitudinal strain and high free radical quinones
sensitivity cardiac components better at predicting cardiotoxicity

peroxidation cardiac
sarcoplasmic reticulum
loss of high-affinity
Ca+2 binding sites

Excess
Endomyocardial biopsy showing loss
intracellular Ca+2
of myofibrils and vacuolization
of cytoplasm disrupt actin & myosin
Ca+2 displacement of
Normally, we have striated heart muscle but in this mitochondrial ATP
case, there are vacuoles (necrosis of the heart
muscle)

Cardiotoxicity 53
The independent predictors of cardiotoxcity following administration of chemotherapy drugs:
1. Decrease LV ejection fraction (Ef) and LV longitudinal strain
2. Increased BNP and decreased LV Ef
3. Detection of Troponin Tcardiac and increased BNP
4. Decreased LV longitudinal strain and detection of Troponin Tcardiac

Correct: 4
Toponin T is released when you have damage to the cardiac muscle. LV longitudinal strain: measure of
active shortening of the ventricles when they contract. When the heart contracts, it changes its shape, the
muscles shorten. By measuring that shortening, you can test whether the heart is really functioning properly
when it contracts. Subtle test versus LV Ef which drops when the heart is really damaged. The longitudinal
test is before that much damage is done.
Bleomycin
This is cell-cycle specific

54
 The BEP Regimen for Lance
Drug
Bleomycin Day 2 Day 9 Day 16
Etoposide Day 1-5
Platinol/ Cisplatin Day 1-5
1 7 14
21 Time (Days)

Identify which of the drugs are cell-cycle

specific and cell-cycle non specific
Discuss the advantage of intermittent dosing
Discuss the pharmacological effect of each drug
55
 Mechanism of Action: Bleomycin
Chelates metals & binds to DNA
Forms bleomycin-DNA-Fe+2 complex
Chelates metal ions (Fe2+),
then binds to the DNA. oxidation
Forms bleomycin-DNA-Fe
complex. Undergoes
oxygenation -> active anti-tumor Bleomycin-DNA-Fe+3
complexes formed that damage
the DNA activated complex
Generates free radicals that
are very destructive. Causes
single breaks and double-
stranded breaks, peroxidation Generate free radicals
of membrane lipids (not functional anymore)
and oxidation of purine & pyrimidines =>
NO replication of the DNA
Single- and double-stranded breaks in DNA, peroxidation
of membrane lipids, oxidation of purines & pyrimidines

56
 Bleomycin: Pharmacokinetics
Pharmacokinetics:
Administered IV
Inactivated in normal cells by aminohydrolase low levels in lung
and skin -thats
there are high levels of the enzyme in majority of normal cells except for lungs and skin so
why theres toxicity related to bleomycin in lungs and skin
Parent dug eliminated by renal excretion

Therapeutic consideration:
Requires adjustment in patients with kidney dysfunction
B/c the longer the drug stays in the system, the more of it converted to the active form -> more toxicity

57
 Bleomycin: Toxicity
Pts start off with dry cough that develops into rales.
Results in infiltration of the cells called fibroblasts?
That makes the lungs very stiff -> pulmonary fibrosis
Toxicity: This is irreversible
Pulmonary toxicity b/c not inactivated by the enzyme that break up the
!
drug b/c not many inactivating enzymes in the lungs
Pulmonary Toxicity - pulmonary fibrosis
Skin Toxicity hyperpigmentation, hyperkeratosis,
erythema and ulceration
Low levels of the drug-inactivating hydrolase enzyme
Myelosuppression - RARE

The risk of pulmonary toxicity induced by

Bleomycin is dose-, age- and kidney
Older age, higher cumulative
function-dependent dose and bad kidney fxn ->
higher risk of toxicity
58
 Pulmonary Fibrosis:
Showing all the fibrosis thats occurred in the lungs.
Can see it better in a CT scan

A trichrome stain highlights the

Honey comb lung as sign of
collagenous connective tissue lung fibrosis in high
of pulmonary fibrosis in blue. resolution computer
tomography
http://library.med.utah.edu/WebPath/
LUNGHTML/LUNG028.html http://images.google.com/imgres
 Mechanism of Action: Dactinomycin

Intercalation of DNA
Inhibits DNA & RNA
synthesis
Single strand breaks
through
b/c of
Free radical formation

DNA damaged and no longer can replicate in the S

phase of the cell cycle -> prevent growth of cancer cells

60
 Dactinomycin: Pharmacokinetics
Administered by intravenous injection
It is excreted in both the bile and urine
Dactinomycin does NOT cross the blood
brain barrier so not useful for treating brain cancers

Many chemotherapeutic drugs are IV b/c of the chemistry

61
 Dactinomycin: Toxicity
Toxicity:
Big effect on the GI
Anorexia, nausea, and vomiting begins a few
hours after administration
Myelosuppression
lower end of the GI tract (rectum and anus) becomes highly inflamed
Proctitis, diarrhea, oral ulcerations
Dermatological toxicities alopecia,
erythema, and desquamation

62
***Just FYI the ones she wants us to know, she will tell us

Mechanisms of resistance to antibiotics

Increased drug efflux

Increased glutathione peroxidase activity
- this enzyme is responsible for
detoxifying free radicals
Decreased topoisomerase II
Decreased cytochrome P-450 activity

63
Correct statement regarding antitumor antibiotics:
1. All produce cardiotoxicity
2. All cause free radical-mediated DNA strand breakage
3. Anthracyclines cause pulmonary fibrosis
4. All cause myelosuppression

Correct: 2
Anthracyclines (Doxorubicin Daunorubicin Idarubicin Epirubicin) do not cause pulmonary fibrosis.
Bleomycin causes pulmonary fibrosis.
All are not cardiotoxic. Anthracyclines can cause cardiotoxicity
All do not cause myelosuppression - bleomycin doesnt

The risk of pulmonary toxicity induced by Bleomycin is dose-, age-, and kidney function related. TRUE
Antitumor Antibiotics: Clinical Uses
Acute leukemias
Solid tumors
Rhabdomyosarcoma
Wilms tumor in children

64
*** Know these toxicities

Summary of Antitumor Antibiotics Toxicities

Drug Class Toxicities Specific Toxicities

Bleomycin Skin toxicity, alopecia Pulmonary fibrosis

Bone marrow suppression,
Hepatotoxicity, vomiting,
Dactinomycin
diarrhea, proctitis, oral
ulceration

Bone marrow suppression,

Doxorubicin
cardiotoxicity, vesicant

Doxorubicin liposomal Hand-foot syndrome

65
Camp et al., 2007; Polovich et al., 2009; Wilkes & Barton-Burke, 2008;Oncology Nursing Society.
 Summary: Antitumor Antibiotics
Anthracyclines, bleomycin and dactinomycin damage
DNA
Mechanisms include DNA intercalation,
topoisomerase inhibition and free radical formation
Anthracycline causes chronic cardiotoxicity which is
cumulative
dose-dependent and is a powerful vesicant causing extravasation injuries
Bleomycin causes skin toxicity and pulmonary
damage which can be irreversible. Drug causes little
myelosuppression
Dactinomycin causes rapid onset nausea, vomiting
and acute myelosuppression
 Part II Conventional
Chemotherapeutic Drug Classes

Learning Objectives for Each Drug Class :

!
Discuss the sites of action of antineoplastic drugs
Identify which drugs/groups are CCS or CCNS
Know the drug names within each class
Compare and contrast the pharmacology of each class (or
drugs within each class) of chemotherapeutic agents:
Mechanism of action
Pharmacokinetics
Toxicities common and unique & mechanisms of toxicities
Mechanisms of resistance

67
Chemotherapeutic Agents that Damage DNA

Cytotoxic Action Alkylating agents

on DNA Platinum compounds
! Antimetabolites
! Antitumor antibiotics
! Topoisomerase inhibitors

Topoisomerase inhibitors:
In general are Cell-Cycle Specific Agents

68
 Relating Chemotherapeutic Agents to Cell Cycle
Damage the DNA -> cancer cells Antibiotics + Topoisomerase
cant proliferate
Act in S and G2 phase
inhibitors
Antimetabolites
S
(2-6h)
G2
(2-32h)
Vinca alkaloids
M
(0.5-2h) Mitotic inhibitors
Taxoids

Alkylating agents, platinum compounds, cell signaling inhibitors

G1
(2-h)

G0
69
 TOPOISOMERASE INHIBITORS
Topoisomerase I Inhibitors (Campothecan plant alkaloids):
Irinotecan (CAMPOSTAR) These drugs were originally isolated
from Capothecan tree in China
Topotecan
!
Topoisomerase II Inhibitors (Podophyllotoxins):
Etoposide Originally extracted from Mayapple

Teniposide

70
 Function of Topoisomerases I & II
When DNA helix has to unwind to replicate, it causes a lot of strain on the DNA. Have to prevent the strain
otherwise DNA will break. Natural enzymes inside the body (Topoisomerases) that prevent that strain. Topo I
make a little cut in the DNA strand and re-seal the DNA strand. This is very fast. Similarly, Topo II make a double-
strand break and cut on both strands and re-seal almost immediately. Very important enzymes

!
Maintain normal structural topology of DNA
Relieve the torsional strain caused by unwinding of DNA via strand
breaks
Topoisomerase I breaks and reseals single-stranded DNA
Topoisomerase II breaks and reseals double-stranded DNA
71
 Irinotecan: Mechanism of Action
DNA helix unwinding and being replicated DNA polymerase DNA
here replicating polymerase
the DNA

Topo 1 Irinotecan
supercoils happen and Replication fork (black oval with C)
topo I relieves that strain Binds to topo and
prevents it from
re-sealing the strand
thats been cut by
Topo
Topo relieves the supercoil DNA polymerase is still
here moving forward and at
the front, the DNA has double-strand
cuts. This DNA polymerase
pushes right into the DNA
DNA breaks
and breaks it up !
So there are multiple
DNA strands -> apoptosis
cant repair ->
no DNA to progress
www.australianprescriber.com into cell cycle

a. Normal function of topoisomerase I b. Irinotecan mechanism

Nicks DNA backbone releases the Binds topoisomerase I-nicked DNA
torsional strain of advancing replication complex
fork Prevents religation of the nicked strand
Religation of nick and the release the enzyme.
Irinotecan: Pharmacokinetics
Implications of these pharmacokinetics
in the tx. *excreted by the kidney
Irinotecan is a PRODRUG. Must be
converted to the form that has antitumor
activity. Converted in the liver by
carboxylesterase enzyme in liver.
This active form (SN-38) is really potent.

Understand how the parent drug and the

metabolite are excreted in the body.
Parent drug in the liver is oxidized This has antitumor
by CYP3A4 and that form is activity
excreted by the kidney. Thats *Excreted in the bile
how you get rid of the parent drug which has no antitumor activity.
SN-38 that has antitumor activity goes through further metabolism
in the liver and is glucuronidated by the UGT 1A1 enzymes -> that
metabolite is then excreted in the bile.
Irinotecan = prodrug, requiring activation to SN38 via
carboxylesterase enzyme in liver
SN38 = active metabolite = topoisomerase I inhibitor
T1/2 of SN38 is longer than topotecan
Oxidative hepatic metabolism via CYP3A is important route of
elimination for irinotecan
Glucuronidation via UGT 1A1 for SN38 metabolite***
Polymorphisms in UGT1A1 affect
irinotecan therapy

Some people have mutations in UGT1A1

enzyme and SN-38 can no longer be
glucuronidated and excreted in the
bile -> toxicity. If you carry a mutation
in this enzyme, you will develop diarrhea
thats so severe that it can be
life-threatening and can develop 74
neutropenia which can also be life-threatening Vol1, 99-108 (2001)
Topoisomerase Inhibitors: Toxicity
Irinotecan
MYELOSUPPRESSION
Diarrhea - can be severe- can happen
in pts who dont
Flu-like symptoms have a mutation too.
Somnolence, Confusion Loperamide given to control
the diarrhea. If you let the diarrhea
Cholinergic syndrome progress, can become very severe -> lose
too many electrolytes and fluids -> arrhythmias
Inhibits acetylcholinesterase
This leads to high levels of acetylcholine -> Lacrimation, salivation, sweating, slow HR, diarrhea
If these pts start with loose stools -> must given them anti-diarrheal agent b/c it can get really bad

Therapeutic consideration:
Adoption of intensive loperamide regimen starting at onset of any
loose stool that begins a few hours after Irinotecan therapy

75
Etoposide

76
Etoposide: Mechanism of Action
Topo I = one strand breakage
Topo II = double strand breakage

Etoposide binds to toposiomerase II and

stabilizes the transient DNA-
topoisomerase II complex and prevents
the enzyme from resealing the double
break in the DNA.
Block in the late S-G2 phase
double-strand
binds to Topo II DNA breaks apoptosis
(DNA damage)

77
 Etoposide: Pharmacokinetics

IV or oral
Oral bioavailability varies greatly between
individuals. Problem: underdosing or
overdosing
Etoposide is primarily eliminated
(Can NOT be given if pts CrCl <20. Parent drug
unchanged in the urine iseffect)
the active form of the drug that has antitumor

There is a synergistic drug reaction with

platinum compounds
Frequently administered with cisplatin

78
Topoisomerase Inhibitors: Toxicity
(if neutrophil count is so
low -> cant fight off
Etoposide infections). If levels
are too low, have to
MYELOSUPPRESSION:
(inflammation of membranes in the mouth)
NEUTROPENIA delay the next schedule
of this drug
Mucositis - high doses b/c affecting cells in GI tract
Hypersensitivity, g-i problems, pulmonary
symptoms -> SOB not too sure why that happens. Maybe due to the additives that are
in the formulation of the drug
cumulative
**Acute non-lymphocytic leukemia dose
related Ifleukemia.
you go over 2g/m2, you have 16% incidence of developing secondary
Can happen 1-3 years after you give this drug. Watch the cumulative
dose of this drug you give.
Causes changes in the chromosomes that can result in leukemia

79
 Mechanisms of resistance to
topoisomerase inhibitors

Increased drug efflux

Decreased activation
Increased metabolism

80
 Topoisomerases: Clinical Uses
Topoisomerase I Inhibitors:
Metastatic carcinoma of ovary
Small cell lung cancer
!
Topoisomerase II Inhibitors:
Lymphomas
Lung, testicular, prostate and uterine
carcinomas

81
A 45 y/o male with refractory advanced colorectal cancer has irinotecan added to his regimen. During tx with
standard dose, he develops neutropenia and severe diarrhea. You suspect he has a mutation.
1. Carboxylesterase
2. Uridine diphosphate glucuronsyltransferase
3. CYP3A

Correct: 2
UGT responsible for adding glucuronidation to the active form and excretion through bile
CYP3A -> responsible for metabolizing the parent drug which has no antitumor activity
Carboxylesterase -> converts ironitecan to active form (SN-38)
***Know these toxicities

Summary of Topoisomerase Inhibitors Toxicities

Drug Class Toxicities Specific Toxicities
Topoisomerase I Inhibitors: Bone marrow suppression,
diarrhea cholinergic syndrome,
somnolence, confusion, flu-like
Irinotecan
symptoms

Topotecan Fever, mucositis

Topoisomerase II Inhibitors: Bone marrow suppression,

nausea and vomiting
mucositis, hypersensitivity
Etoposide reaction, pulmonary toxicity

Teniposide

82
Camp et al., 2007; Polovich et al., 2009; Wilkes & Barton-Burke, 2008;Oncology Nursing Society.
 SUMMARY: ANTITUMOR ANTIBIOTICS &
TOPOISOMERASE INHIBITORS

Differ in structure and mechanism(s) of action,

but are all derived from biological sources or are
derivatives of naturally occurring compounds.
!
Fall into two major subcategories:
topoisomerase inhibitors
free radical generators
! (inflammation of the mucosal
membranes)
Toxicities include myelosuppression, mucositis,
skin toxicities

83
 Part II Conventional
Chemotherapeutic Drug Classes

Learning Objectives for Each Drug Class :

!
Discuss the sites of action of antineoplastic drugs
Identify which drugs/groups are CCS or CCNS
Know the drug names within each class
Compare and contrast the pharmacology of each class (or
drugs within each class) of chemotherapeutic agents:
Mechanism of action
Pharmacokinetics
Toxicities common and unique & mechanisms of toxicities
Mechanisms of resistance

84
Chemotherapeutic Agents that Inhibit DNA
Synthesis
Cytotoxic Action Antimetabolites
on DNA These physically inhibit synthesis of DNA
!
!
!

Antimetabolites:
In general are Cell-Cycle Specific Agents

85
 Relating Chemotherapeutic Agents to Cell Cycle
Inhibit the synthesis of DNA which Antibiotics + Topoisomerase
happens during the S phase of the
cell cycle inhibitors
Antimetabolites
S
(2-6h)
G2
(2-32h)
Vinca alkaloids
M
(0.5-2h) Mitotic inhibitors
Taxoids

Alkylating agents, platinum compounds, cell signaling inhibitors

G1
(2-h)

G0
86
 Antimetabolites
The antimetabolites alter nucleotide synthesis
The antimetabolites are cell specific agents
Structurally resemble natural metabolites
Sub-classified according to metabolite affected
and include:
folic acid analogues
purine analogues
pyrimidine analogues

These alter the synthesis of nucleotides that make up the DNA b/c they resemble the natural metabolites like
purines and pyrimidines and folic acid.
 Building blocks of DNA: purines and pyrimidines

(purine or pyramidine)

88
 know the folate co factors!

Nucleotide Synthesis Overview

3 specific tetrahydrofolates
have essential roles as 1-
carbon carriers in the
synthesis Start with AAs and have to have PRPP.
Same biochemical components.
Uridine monophosphate (UMP)
of DNA precursors: In presence of folate, have inosotyl monophosphate
precurosr made
(IMP) - purine
10-formyl-THF (purines) precursor
5, 10-Methylene-THF
(dTMP)
5,-methyl-THF (tetrahydrofolate)
(methionine)
Body makes nucleotides (purines
and pyrimidines). Need folate as an
important cofactor. Cant make
purines or pyrimidines without folate. folate required

Note the central role of folate as an essential cofactor

in the synthesis of purine nucleotides and dTMP
Antimetabolites: Folate
analogs (folate antagonist)
Methotrexate

90
Methotrexate: Mechanism of Action
Interferes with Methotrexate (MTX) taken
tetrahydrofolate (FH4) into cell via reduced-folate
metabolism carrier (RFC)
FH4 functions as active transport
cofactor in synthesis Polyglutamation occurs in
of precursors of DNA tumor cells (MTX-PGs)
Facilitates accumulation of
(thymidylate and inside the cancer cell (retains in the
MTX cancer cell for longer and inhibit synthesis)
purines) and RNA Allows selective retention of
(purines) MTX
Looks like a folate analog so its taken up by folate
Cell cycle specific carriers found in the cell membranes of normal and
cancer cells
drug
S-phase b/c they inhibit DNA
synthesis
 Methotrexate: Mechanism of Action
MTX inhibits thymidylate synthesis
=> Primary target
and therefore taken away a basic
for MTX. Inhibits this
building block in the DNA and disrupt
enzyme.
DNA synthesis.
When you produce thymidylate,
have a precursor molec.
dUMP which is converted to
TMP. In this conversion, the
thymidylate synthase is
needed. Need methylene FH4
cofactor. FH4 oxidized and need to
convert to the reduced form and
need dihydrofolate reducatse
is needed to do that -> to
continue converting dUMP to
TMP.

MTX is depleting the cofactors

needed

Primary target of MTX is dihydrofolate reductase (DHFR)

Affinity of MTX for DHFR greater than FH2
Depletes FH4 cofactors 5-10 methylene tetrahydrofolic acid and N-10 formyl
tetrahyrofolic acid
MTX-PGs inhibit thymidylate synthase
92
 Methotrexate: Mechanism of Action
Start with an AA and pyrophosphate and eventually you get to the purine precursor. Polyglutamate MTX inhibits
GAR tranformylase. In the presence of formyl FH4 and GAR, the enzyme converts it to AICAR metabolite and FH4.
These are then converted to IMP and FH4 by AICAR transformylase. Inhibiting the precursor IMP for purines by
inhibiting GAR and AICAR transformylases. No purine = inhibiting DNA synthesis

**Know the enzymes being

inhibited by MTX in purine
vs pyrimidine synthesis

MTX-PGs inhibit thymidylate synthase and

aminoimidazolecarboxamide(AlCAR) transformylase
Depletes TMP
Deplete purine synthesis
93
 Methotrexate: Pharmacokinetics
Renal excretion: Parent
(90%) and metabolites (7-
OH MTX and DAMPA)
Complex pattern of PKs
1st phase tissue distribution
2nd phase renal clearance
(T1/2 = 2-3 hr)
3rd phase renal clearance
(T1/2 = 8-10 hr)
Therapeutic consideration:
Renal insufficiency requires
dose adjustment
Co-administration of Rx that
reduce renal blood flow, are
nephrotoxic or weak acids
delay excretion of MTX
When you give this drug, make sure the pt is well hydrated. The drug is distributed to the tissue (cancer and
normal cells) in the first phase. Then its cleared by the kidney in two phases. 2nd phase - half life is 2-3 hrs.
3rd phase - half life increased b/c it takes a long time for the kidney to get rid of this drug. Think about anything
that will delay the excretion of MTX -> increased toxicity

Drugs that decrease renal blood flow (ACEI and NSAIDs) -> half life of the parent MTX thats causing the cancer
kill increases.

Drugs that are weak acids (aspirin) delay the excretion of MTX

Also, avoid giving drugs that are nephrotoxic b/c synergistic nephrotoxicity will occur e.g. platinums (cisplatin)
cancer drugs

Have to be really aware of these criteria when giving MTX

Making urine alkaline will reduce the MTX toxicity

 Methotrexate: Toxicity
effect on epithelial lining of the GI tract -> ulcers form
in the pts mouth
Ulceration:
gastrointestinal and
oral mucosa
Bone marrow
suppression
Hepatotoxicity - reversible
CNS toxicity(tingling in the hands & feet)
high doses
High-dose MTX Stomatitis
potential for
Nephrotoxicity:
Precipitaiton of RX in Therapeutic consideration:
acidic urine Vigorous hydration and urinary alkalinization
High doses: concentration required prior to treatment with MTX to reduce
exceeds MTX solubility incidence of nephrotoxicity
7-OH-MTX @ high dose Administration of Leucovorin (folinic acid; 5
therapy -formyl-THF) to limit toxic effects of high-dose
If you give MTX in high doses, may find that that methotrexate in normal cell
!
drug can precipitate out of the urine and cause
a lot of kidney damage. 7-OH-MTX metabolite
is also damaging to the kidney
 Leucovorin (folinic acid) Rescue
Rescues normal cells from
the adverse effects of
methotrexate caused by
inhibition of production of
reduced folates.
Leucovorin provides the normal cells
thymidylate
synthetase
with an alternate source of folic acid

Gives the normal cells another form of TH4 so they can go on to

produce purines and thymidylate in the presence of this anti-cancer
drug. Lets say we have a cell in the bone marrow and want to
continue that DNA synthesis & produce neutrophils etc. TH4
in the form of folinic acid bypasses the conversion blocked by MTX
and directly provides TH4 for the production of thymidylate and
purines in the normal cells. Normal cells take up the folinic acid
more rapidly than the cancer cells.
No need to remember

Mechanisms of resistance to MTX

Altered cofactor or
metabolite levels
(increased salvage
pathways.
Gene amplification (DHFR)
Increased drug efflux
Polyglutamated MTX allows for drug to stay in the cell longer resulting in a better chemo response. TRUE

Identify the toxicities associated with MTX:

1. GI desquamation
2. Mucositis/stomatitis
3. Nephrotoxicity
4. Bone marrow suppression
5. Inadequate leucovorin rescue
6. All of the above

Correct: 6
GI desquamation is sloughing off the cells in the GI tract -> killing those cells -> stomatitis

Select the correct statement regarding MTX:

1. S-phase specific
2. Inhibits DHFR
3. Enters cell via a reduced-folate carrier
4. All of the above answers are correct

Correct: 4
 Capecitabine

Antimetabolites: Pyrimidine
analogs
5-Fuorouracil and 5-Fluorodeoxyuridine
ne

Capecitabine and Gemcitabine

Cytarabine (Ara-C)

98
 Relating Chemotherapeutic Agents to Cell Cycle
Work on the S phase of the cell cycle
Antibiotics + Topoisomerase
b/c they inhibit DNA inhibitors
Antimetabolites
S
(2-6h)
G2
(2-32h)
Vinca alkaloids
M
(0.5-2h) Mitotic inhibitors
Taxoids

Alkylating agents, platinum compounds, cell signaling inhibitors

G1
(2-h)

G0
99
 5-Fluorouracil: Mechanism of Action

Facilitated uracil
!
transport mechanism

Pyrimidine analog

S/G1 cell
cycle phase

Requires enzymatic conversion to active nucleotide metabolite 5- dFUMP

to exert cytotoxic effects TMP
5-FdUMP: Inhibits thymidylate synthetase and blocks synthesis of TTP
KEY MECHANISM
5-FdUTP incorporated into DNA - ? effect
5-FUTP incorporated into RNA disrupts function
also KNOW ENZs!
5-FU metabolized to the active form. 5-FU taken up by a carrier into cancer and normal cells. Multiple pathways
to convert the drug to active metabolite. The active metabolite, 5-FdUMP, becomes a substrate for thymidylate
synthetase. This enzyme converts dUMP to dTMP. If this enzyme is inhibited -> not going to produce that
pyrimidine -> removing an essential building block for DNA synthesis

Also converted to 5-FUTP which is incorporated into RNA and stops RNA synthesis b/c theres a big molec.
inhibiting in the RNA.

Not sure if 5-FUTP is further metabolized to 5-FdUTP which also can block DNA (Nice to know)
Given orally. Taken up and goes to the liver. Liver starts to break it down into its components. Eventually you get to the components
into the blood stream and goes inside the cancer cells. In cancer cells, there are high conc. of thymidyine phosphorylase.

Capecitabine: Mechanism of Action

Precurosr DFCR converted to DFUR and then converted to 5-FU by thyidine phosphorylase which is the active metabolite. 5-FU and
capecitabine are prodrugs b/c need to convert them to active metabolites to kill the cancer cell.

S-phase specific

CE = Carboxylesterase
CyD = Cytidine deaminase
DFCR = 5-deoxy-5-fluorocytidine
DFUR = 5-deoxy-5-fluorouridine

Oral, prodrug - Liver conversion to 5 DFUR

Tissue conversion 5 DFUR to 5-FU tumor
specific
 5-Fluorouracil: Pharmacokinetics
Capecitabine is an orally available cytosine analog
converted to 5-FU in vivo

5-FU absorption after oral doses is unpredictable and

incomplete. Given IV

T1/2 of 5-FU is 10-20 min (Rapid clearance, must be

given as continuous IV infusion) NOT bolus

5FU & Capecitabine:

Catabolic degradation occurs in the liver the drug is
inactivated to dihydrofluorouracil by dihydropyrimidine
dehydrogenase (DPD).

Converted to -fluoro--alanine with the release of CO2

-> thats why the pts who take this drug have a strange breath. Metabolites come out in the breath so breath tests
have been developed to test for toxicity
102
Metabolite appear in urine, CO2 eliminated n breath
 5-Fluorouracil/ Capecitabine: Toxicity
Mucositis: inflammation of the mucosal membrane
Myelosuppression,
Mucositis, Diarrhea
more frequent with bolus
regimens
Hand-foot syndrome
More frequent with
Capecitabine
Severe toxicity with
Dihydropyrimidine
dehydrogenase (DPD)
deficiency
Desquamation of the skin (skin starts to come off on
the hand and feet)

The toxicity is worse if you have a deficiency in the DPD

enzyme so these people are more prone to the toxic
effects of this drug.

Desquamation of the soles of the feet =

Hand-foot syndrome, a.k.a.
103
palmar-plantar erythrodysesthesia syndrome
Nice to know

Mechanisms of resistance to 5-FU

Loss or decreased activity of 5-Fluorouracil converting
enzymes
Amplification of thymidylate synthetase
Altered activity of thymidylate synthetase the enzyme
is no longer inhibited by 5-FdUMP
Increased 5-Fluorouracil catabolism

104
Cytarabine (Ara-C): Mechanism of Action
Must be converted inside the cancer cell to the active form. Converted to AraCTP (phosphates added -> active metabolite that will
inhibit DNA synthesis -> it is an inhibitor of DNA polymerase which is required to synthesize DNA)

Cytarabine arabinoside is a pyrimidine antimetabolite

Ara-C is activated by kinases to AraCTP
The compound is readily taken up by cells and
converted to the triphosphate form (araCTP). araCTP
AraCTP is an inhibitor of DNA polymerase
Inhibiting purines and pyrimidines b/c
inhibiting DNA polymerase

105
 Ara-C: Pharmacokinetics
Only 20% of oral doses reach circulation (must be given IV)
Inactivated by cytidine deaminase

Renal elimination (once inactivated by cytidine deaminase)

-> toxicity
T1/2 varies with infusion schedule (Continuous>Rapid)

Depot liposomal formulations (DepoCyt )

Drug in the middle of the liposomal formulation
direct administration into the CSF(intralumbar or intraventricular)

longer half life (82.4 hours)

less frequent dosing schedule

106
 Ara-C: Toxicities
- can cause a very fast and severe reduction in
Potent myelosupressive agent the WBCs and platelets -> pt really prone to
infections.

May produce acute, severe, leukopenia,

thrombocytopenia, and anemia with striking
megaloblastic changes

Cerebellar toxicities associated with the depot formulation

(loss of full control of bodily movements)

Slurred speech and ataxia

Following intrathecal administration

Use with caution in patients with poor renal function

107
Converted to the metabolite that will replace the cytodine building blocks imp. for DNA synthesis -> stops DNA
synthesis b/c not functional pyrimidine. Give the drug, taken up by transporter inside cancer cell -> by kinases, it
will attach the phosphates to the molec. -> taken up into the DNA -> stops synthesis

Gemcitabine: Mechanism of Action

NTK the differences between all these drugs and MOA and how they bind.

A difluoro
analog of
deoxycytidine

The triphosphate analogue of gemcitabine

replaces cytidine duringDNA replication
108
When gemcitabine taken up into cell, it can be deactivated by deoxycytidine deaminase rapidly -> depleting
potential cancer-killing form of the drug. This is a limitation of gemcitabine as its given -> rapidly deactivated.
Liposomal gemcitabine increases the pharmacological activity of the drug

Liposomal gemcitabine
Main limitation of gemcitabine: rapid
inactivation by the deoxycytidine
deaminase enzyme
Solution: encapsulation in liposomes:
pharmacological activity
plasma half-life
tumor localization
side effects (more goes into tumor, less into normal cells)
Nice to know

Mechanisms of resistance
Self-study
Capecitabine
Ara-C
Gemcitabine

110
Antimetabolites: Purine analogs

Mercaptopurine & Thioguanine

These are prodrugs too

111
 Mercaptopurine:
Mechanism of Action:
!
Undergoes enzymatic Thioguanine also
conversion VIA Hypoxanthine- converted by this
guanine HGPRT same enzyme ->
phosphoribosyltransferase resistance to
(HGPRT) to Thioinosinic acid mercaptopurine will
lead to resistance
(thio-IMP) in the liver to thioguanine.
Thio-IMP has multiple actions:
(TIMP)
Feedback inhibition of de novo
purine biosynthesis active metabolite
(TIMP) Inhibits enzymes that convert
IMP to purine nucleosides AMP Thio-GMP
precursor of purine synthesis
& GMP which are the purines
(TGMP) RNA
DNA incorporation -
In the liver, HGPRT enzyme converts the parent drug AMP
to 6-thioinosinic acid (TIMP). This is the anti-cancer IMP GMP
metabolite. -
Thio-guanine monophosphoate incorporated into Feedback inhibition of
DNA and RNA phosphoribosylamine
Synthesis de novo
purine synthesis 112
Thioguanine: Mechanism of Action:
!
Similar to 6-MP

Thioguanine

113
When you give the cancer therapeutic agents, pts get hyperuricemia (high levels of uric acid). Normally txed with
allopurinol so often allopurinol is co-administered.

Mercaptopurine: Pharmacokinetics
If someone on allopurinol and getting mercaptopurine -> increased toxicity. Reduce dose of mercaptopurine.

Oral first pass Major route of drug

metabolism via xanthine eleimination in the liver via 2
oxidase (XO) reduces enzymatic pathways:
bioavailability
Intravenous rapid 6-MP
metabolic degradation
via XO and Thiopurine S-
methyltransferase
(TPMT) can be metabolized in erythrocytes
b/c they also have TMPT
Erythrocyte TMPT TMPT 6-thiouric acid
(inactive)
Mutation in TPMT -> toxicity b/c cant deactivate the
parent drug -> high levels XO
Therapeutic consideration:
Oral dose of mercaptopurine
should be reduced in patients
receiving Allopurinol (XO 6-methyl MP
(active) inactive
inhibitor)
114
 Mercaptopurine: Toxicity
Myelosuppression
Hyperuricemia and gout -acid
its a purine analog. Killing all the cells -> high levels of uric
-> gout
Jaundice and hepatic enzyme elevation b/c mercaptopurine has a high
metabolism by the liver
Resolves upon discontinuation of therapy
Relationship of PKs with enhanced toxicity:
Thiopurine S-methyltransferase (TPMT) deficiency
(Caucasians)
Mutation in the TPMT enzyme -> more prone to toxic effects of this drug
Mutation mostly occurs in Caucasians

115
 Individuals with a deficiency in the
metabolizing enzyme TPMT, or those with
a mutation in the enzyme that results in it
having reduced activity, are prone to
myelosuppression toxicity as a result of
excess 6MP accumulation.
The FDA approved a test to identify
whether individuals have TPMT deficiency,
and testing is recommended.

116
Nice to know

Mechanisms of resistance to purine

analogs

Decreased HGPRT
Increased metabolism

117
 Which of the following primarily target
thymidylate synthetase
1. Methotrexate
2. 5-Fluorouracil
3. Mercaptopurine
4. Thioguanine
Both MTX and 5-FU target thymidylate synthetase

Be familiar with the MOA. Create a table for yourself to see where all similar MOAs are.

0 of 30
 Summary of Antimetabolite toxicities
Drug Specific Toxicities Class Toxicities

Folate Analogs
Bone marrow suppression, GI &
Methotrexate CNS toxicity, renal damage
oral toxicities, hepatotoxicity
Purine Analogs
Bone marrow suppression, gout
Mercaptopurine
and jaundice
Thioguanine

Pyrimidine Analogs
Bone marrow suppression,
Capecitabine & Fluorouracil Hand-foot syndrome nausea and vomiting,
stomatitis, diarrhea, fever,
Cerebellar toxicity,
Cytarabine
conjunctivitis

119
Camp et al., 2007; Polovich et al., 2009; Wilkes & Barton-Burke, 2008;Oncology Nursing Society.
 Antimetabolites: Clinical Use
Folate analogs
Acute lymphoblastic leukemia (ALL), lymphomas,
osteosarcoma, and rheumatoid arthritis.
Pyrimidine analogs
Leukemia
Colorectal cancer
Solid tumors- head, stomach, breast, pancreas, esophagus,
liver, and neck
Purine analogs
Childhood acute leukemia

120
 SUMMARY: ANTIMETABOLITES
Many are transformed (spontaneous or metabolism) to the
active forms. The administered drug may not be the
therapeutic agent. **Know which ones are prodrugs
!
Primarily interfere with DNA and RNA synthesis (& indirectly
with protein synthesis). They are generally most active during
S-phase of the cell cycle.
!
Many have more than one site of action in biosynthetic
pathways.
!
Primary cellular processes disrupted are DNA and RNA
synthesis. The site(s) of drug action are proteins (enzymes)
involved in DNA and RNA biosynthesis.
!
Primary toxicities include myelosuppression and mucositis.
121
July 9, 2015

Chemotherapeutic Drugs that

Act on the Mitotic Spindle

MICROTUBULE INHIBITORS:
Taxanes:
Paclitaxel, Docetaxel, Ixabepilone
Vinca alkaloids:
Vinblastine (VBL), Vincristine (VX), Vinorelbine (VRB)

122
 Relating Chemotherapeutic Agents to Cell Cycle
Antibiotics + Topoisomerase
inhibitors
Antimetabolites
Work in the M phase:
S
Disrupt mitosis.
(2-6h)
G2
(2-32h)
Vinca alkaloids
M
(0.5-2h) Mitotic inhibitors
Taxoids

Alkylating agents, platinum compounds, cell signaling inhibitors

G1
(2-h)

G0
123
 Mitosis: Role of Microtubules
During previous cycles, the cell has been preparing and increasing number of proteins
and synthesizing DNA so you eventually you get two sets of chromosomes. One set
goes to one cell and the other set goes to the other cell.

Microtubules are very dynamic. They

are constantly changing. Either going into the
If these microtubules are inhibited:
assembly (polymerization) phase which
prevent mitosis and proliferation but
is lengthening or one side can
because of other functions, specific
go into the disassembly
side effects will be seen in the body
phase or
the depolymerization phase which
is shortening. Microtubules shorten Polymerization Depolymerization
and lengthen to pull the chromosomes apart
(specialized proteins - dimers)
Mitotic spindle - made up of microtubules - separates the chromosomes
Microtubules are in constant dynamic motion - continuous assembly and
disassembly by means of tubulin polymerization and depolymerization
Microtubules are required to form the mitotic spindle. Also maintain cell
shape and organelle location, mediate intracellular transport and
secretion, neurotransmission and axonemal flow.
124
 Mitotic Inhibitors: Mechanism of
Action
Interfere with microtubule synthesis and mitosis -> prevent further
proliferation of the cancer cells

Mitotic Inhibitors interfere with mitosis arrest cells in M phase

Make microtubules and eventually stabilized -> one end shorter and one end that lengthens.
Shortens b/c of depolymerization and lengthens because of polymerization of these microtubules
Mitotic Inhibitors: Mechanism of Action
Tubulin dimers Microtubules

Steady State

Taxanes Continued polymerization

highly stable dysfunctional
bind to tubuIin and microtubules
prevent Mitotic spindle grows and
depolymerization -> prevent shortening of the microtubules lengthens and becomes
but have no effect on the other side dysfunctional

Dissolution mitotic spindle

Vinca Alkaloids
!
bind to tubulin
and block tubulin
polymerization
126
-> block the lengthening of the microtubules but the other end of the microtubule continues to shorten. Microtubules
start to break up b/c getting shorter and shorter fragments -> cant pull the chromosomes apart -> have mitotic arrest
 Microtubule Inhibitors in Action
Longer microtubules in green Short fragments in green

Paclitaxel Vinblastine
 Taxanes: Pharmacokinetics
IV administration
Poor water solubility necessitates inclusion of surfactant
vehicles in formulations
Paclitaxel very limited solubility
-> allows the drug to be
Dissolved in cremophor (polyethoxylated castor oil) and ethanol distributed
Problem: hypersensitivity
Docetaxel more soluble than paclitaxel rxn to this. Can be given
**Know which one will cause more
Dissolved in polysorbate 80 hypersensitivity rxns a steroid to prevent that
associated with a lower incidence of hypersensitivity reactions than paclitaxel
dissolved in cremophor
These molecs. are big and
Docetaxel have poor solubility so Paclitaxel
must be given IV in a
formulation that can be
taken into the body and
distributed

128
Vehicle was changed so theres better distribution and less hypersensitivity

nab-Paclitaxel: Pharmacokinetics
Paclitaxel protein-bound particles (ABRAXANE)
Patented albumin coating of cytotoxic drug provides
advantages:
Albumin is a natural carrier of hydrophobic molecules -
eliminates the need for solvents and solvent-associated
toxicities -> decreases the hypersensitivity rxns b/c no cremaphor anymore
Allows 49% higher dose than solvent-based paclitaxel
without the need for premedication
eg, steroids, antihistamines -> no need to give these

Faster dose administration in 30 minutes versus 3 hours

with solvent-based paclitaxel -> better distribution with this
Concentrates cytotoxic agent at tumor site
http://abraxane.com/professional/phase_III_efficacy/Phase_3_Solvent-free_Therapy.html
In that specialized coating, they put something else to ensure that whatever it carries will go directly into the
tumor.
Faster administration
Less hypersenstivity rxns 129
Concentrates at the site of the tumor
 Taxanes: Pharmacokinetics
Eliminated in stool:
Hepatic metabolism by CYP2C8 or CYP3A4
Biliary excretion into stool
!
Dose modification in patients with hepatic
dysfunction

130
Mitotic Inhibitors (Taxanes): Toxicity
Paclitaxel, Docetaxel , Ixabepilone
MYELOSUPPRESSION especially Neutropenia (Ix,D>P) - also
with Abraxane (Ixabepilone worst for the myelosuppression and raised liver enzymes)

Alopecia
Hypersensitivity reactions (Ix, P>D)
Requires pre-medication (any three of these drugs)
Microtubules imp for cellular transport -> inhibiting them results in muscle pain
Myalgias (muscle pain)& sensory neuropathy (Ix,P)
Severe tingling in the hands (Ix,P)
Fluid retention (D) and the feet -> very sensitive
In the axon or any nerve cell, need
microtubules cells to transport things
from cell body to the end of the neuron

131
Vinca Alkaloids: Pharmacokinetics
Eliminated in stool:
Hepatic metabolism by CYP3A4 or CYP3A5
Biliary excretion into stool
!
Dose modification in patients with hepatic
dysfunction

132
Mitotic Inhibitors (Vinca Alkaloids): Toxicity

Vincristine: -> CNS symptoms like the neuropathy b/c of the way it inhibits
microtubules and drug design. You will know when theres neurotoxicity b/c
NEUROTOXICITY tingling in hands and feet and eventually will lose the reflexes
Vesicant -> extravasation issues (leakage of drug to the surrounding tissues -> painful ulcers)
NO myelosuppression -> useful in combining
Alopecia, skin rash and fever with other regimens that are myelosuppressive.
Vinblastine:
MYELOSUPPRESSION = neutropenia
Hypertension
Mucositis and stomatitis -> b/c affects the high growth fraction cells
Alopecia
Vinorelbine:
Myelosuppression

133
FYI

Mechanisms of Resistance to Mitotic

Inhibitors

Increased efflux
Tubulin mutations

134
Correct statement regarding Paclitaxel:
a. prevents lengthening of microtubules
b. toxic effects are increased in liver dysfxn
c. most potent in causing neutropenia
d. no hypersensitivity reactions upon administration

Correct: b
Metabolized by the liver
Aszibethalon? -> most potent in causing neutropenia
Hypersensitivity rxns happen due to cremaphor
 Summary of Mitotic Inhibitors Toxicities
Drug Class Toxicities Specific Toxicities
Vinca Alkaloids: Mild neuropathies
Vinblastine Bone marrow suppression,
alopecia, hypertension,
mucositis, stomatitis
Vincristine !
Severe neuropathy, fatal,
if given intrathecally.
Alopecia, vesicant, skin
rash, fever
Vinorelbine Myelosuppression
Bone marrow
Taxanes: suppression,
hypersensitivity, alopecia
Docetaxel fluid retention
Paclitaxel myalgia, sensory
Camp et al., 2007; Polovich et al., 2009; Wilkes & Barton-Burke, 2008;Oncology Nursing Society.
neuropathy 135
Mitotic Inhibitors: Clinical Uses
Hodgkins and Non- Hodgkins lymphoma
Acute lymphoblastic leukemia
Ewings sarcoma

136
Summary: Drugs that Act on the Mitotic Spindle

Strictly CCS drugs with arrest in M phase.

The disrupted cellular process is cell division. The
site of drug action is protein (tubulin/
microtubules).
Taxanes
High-affinity Microtubule Binding/ Inhibition of Mitotic
Spindle Function
Myelosuppression & neurotoxicity (Pac, Ix)
Vinca alkaloids
Inhibits Tubulin Polymerization, disrupting mitotic
spindle formation
Neurotoxicity is major problem with Vincristine vs.
myelosuppression with Vinorelbine & Vinblastine
137