Table of Contents

Alkylating agents .................................................................................................................. 6

Nitrogen mustards .........................................................................................................................7
Mechlorethamine ................................................................................................................................................7
Melphalan ............................................................................................................................................................8
Chlorambucil ........................................................................................................................................................8
Cyclophosphamide ...............................................................................................................................................8
Alkyl Sulfonate (Busulfan) ..............................................................................................................9
Cisplatin [IV] ..................................................................................................................................9
Mitomycin C [IV] .......................................................................................................................... 11
Nitrosoureas ................................................................................................................................ 11
Lomustine [PO]...................................................................................................................................................11

Antimetabolites................................................................................................................... 13
Folic acid analogs ......................................................................................................................... 13
Methotrexate (MTX) ..........................................................................................................................................13
Pyrimidine analogs....................................................................................................................... 14
5-Flurouracil (5FU) .............................................................................................................................................14
Capecitabine [PO] ..............................................................................................................................................15
Cytarabine (AraC)[IV] .........................................................................................................................................16
Gemcitabine [IV] ................................................................................................................................................16
Purine analogs ............................................................................................................................. 17
6-mercaptopurine (6MP) ...................................................................................................................................17
6-thioguanine (6TG) ...........................................................................................................................................17
Cladribine [IV] ....................................................................................................................................................18

Tubulin inhibitors ................................................................................................................ 19

Vincristine/Vinblastine [IV] .......................................................................................................... 19
Paclitaxel/Docetaxel [IV] .............................................................................................................. 19
Abraxane ............................................................................................................................................................20
Ixabepilone .................................................................................................................................. 20
Eribulin ........................................................................................................................................ 20
Topoisomerase inhibitor ...................................................................................................... 20
Etoposide .................................................................................................................................... 20
Irinotecan [IV].............................................................................................................................. 21
Anthracycline ...................................................................................................................... 22
Doxorubicin/Daunorubicin ........................................................................................................... 22
Bleomycin [IV] ..................................................................................................................... 23
Cytotoxic anti-cancer drugs
- Many of these drugs will kill cancer cells by inducing apoptosis
- Cells breakdown  fragmentation
- Endonucleases degrade DNA as part of apoptosis

The cell cycle

- G0: no active cell division

- G1: 40% of cells in this
particular phase at any point
in time
o Preparing for DNA
replication, cell
synthesis
 Making
nucleotides
 Enzymes
necessary
 Structural
proteins
- S phase: DNA replication
o S-phase specific agents that act on processes associated with DNA replication
- G2: preparing for mitosis
o 19% of cells in this phase at any particular time
- M phase: mitosis
o 2%
o M-phase specific agents interfere with microtubule functions
- Certain cells can undergo differentiation and take on different characteristics
o Decreased potential for proliferation
 Organs don’t grow infinitely
- During cancer, some cells lose ability to control growth and proliferate, divide much
more rapidly and tumors are formed
- Tumor cells are made up of relatively poorly differentiated cells compared to non-tumor
cells
o Growth fraction:
 Number of cells undergoing proliferation
 Tumors have higher growth potential  high growth fraction
o Agents that block ability to divide, to synthesize DNA, tumors are more
susceptible to that agent because they’re growing faster
 Normal cells with high growth fraction (bone marrow, lining of GI tract,
hair) are also susceptible to these cytotoxic agents
 o Leukemia: blood tumors that cause problems in bone marrow and produce
poorly differentiated cells and
o Solid tumors:
 Growth fraction can vary (1-8%)
 GI tract epithelium – 18$
o Cancer stem cells
 Cells with proliferative capacity (<1% of cells)
 Somewhat resistant to chemotherapeutic agents
 Metastasis
- Gompertzian growth
o Initial exponential growth
 Plenty of nutrition for
growth
o As tumor gets larger, there is
not enough nutrition (↓ blood
supply, ↓ nutrients,
accumulation of toxic
byproducts), tumor growth
slows down
o Can detect tumor cells at 10E9
(1 billion) tumor cells
 At 10E12 cells, the body
can’t survive
 Tumor cells use
up too much
o Infrequent treatment (top) 
not sufficient to attack tumor
o As treatment is given more
often, cell number decreases
over time
 Combination drugs
o Remission – if treatment is effective and no cancer cells can be detected
 Finite period of time
 If tumor doesn’t come back in 5 years, the person is in remission
 5-, 10- year remission endpoints can define efficacy of drugs
o Log Cell Kill Hypothesis – each dose of drug given can kill a constant % of cells
 Very difficult to get rid of every single cell
 The number of cells that are killed is decreasing each time
 Rely on immune system to get rid of last few cells
 Cytotoxic agents so can’t keep giving these drugs; they have
consequences for the patient.
 Use highest dose possible, as often as possible to get the highest % of kill
o Max cell kill
 ↑ % of cells kissed
  Dose-response kill
 Given as often as possible
o Start at 10E12 cells:
 Agent has 99.99% efficiency
 Single dose  10E8 cells left
- Drug resistance
o Primary resistance
 Some cells are not affected to drug even if they’re not exposed to that
drug before
 Resistance prior to drug exposure
 All cells are not the same
o Acquired resistance
 Happens as a response to drug exposure
o Drug combinations can prevent development of resistance
o Gene mutations
 Oncogenes – promote tumor growth
 Tumor suppressor genes – prevent cancer formation
 Mutations in these key genes
 Amplification – cell gains ability to make much more of a protein
o Altered DNA repair capabilities
 Alkylating cells damage DNA
 Repair systems prevent damage during DNA synthesis by DNA
polymerase
 Tumor cells can alter DNA repair capacity
 If damage is getting repaired faster than usual, that drug will not
be effective
o Efflux pumps
 Drug can’t accumulate inside cancer cells at a high concentration for its
mechanism of action to be effective
 Pump drugs out of cell
 P-Glycoprotein
o Increased production of scavengers
 Glutathione (GSH)
 Made up of 3 amino acids – glutamate, cysteine, lysine
 Can interact with oxygen radicals using SH group on cysteine
 Alkylating agents interact with DNA and form ROS that can interact with
GSH
- Optimal efficacy
o Use effective drugs
 Combination drugs that are determined to be effective against a certain
type of cancer cell
 Evaluate relative phenotypes
 To make sure patients won’t have a problem with a specific drug
o Minimize overlapping toxicities
 o Dosing schedule
 Highest dose possible, as often as possible, as safely as possible
 Constant infusion, bolus dose

Alkylating agents
o Covalent attachment of alkyl groups to macromolecules (DNA, RNA, protein)
 Form reactive intermediates and can react with whatever is nearby
o Bis(chloroethyl) amine/ethylenediamine – reactive functional group
 N(CH2CH2-Cl)2
 Ethylenediamine AKA aziridinium ion
o Alkylation of nucleophilic sites ( electron-rich)
 Electrophiles (electron poor groups) are looking to interact with
nucleophiles (electron-rich)
 phosphate, carboxyl, amino, imidazole
o Not cell cycle-specific
 Can cause damage throughout cell cycle
 Alkylation occurs at any time
 Won’t see effect until cell tries to replicate (S phase)

- Nitrogen mustards (toxic)

- Crosslinked DNA – 2 strands can’t separate from each other
- If alkylate 1 site  repair is much more efficient
o If alkylate 2 sites  much more difficult to repair
- Resistance
o ↑ DNA repair capabilities
o ↑ GSH production
o ↓ uptake
 - R group
o Differentiates between different alkylators
o Aliphatic
 More electrophilic (tends to donate electrons)
 ↑ reactivity
 Mechlorethamine: CH3  R group
 Fastest reacting alkylators - T1/2: 15 minutes
 Acts very quickly
o Aromatic group
 More electron withdrawing
 Slower reactivity
o ↑ reactive  ↓ selectivity to tumor cells (react with everything)
 Limit dosage form
- Monofunctional vs. bifunctional alkylators
o Monofunctional agents – form 1 reactive intermediate – can’t crosslink
o Crosslinking (bifunctional)
 Intra-strand – interaction of 2 nucleotides in the same strand of DNA
 Bend (kink) in DNA can disrupt action of DNA polymerase that is
trying to replicate that strand of DNA
 Inter-strand – covalently connecting opposite DNA strands
 Blocks replication
o Mispairing (mono/bifunctional)
 GC
 Alkylate guanine with methylating agent at O6 agent (O6-
methylG)  pair preferentially with T instead of C
 When strand gets replicated: G (O6M)=T 
o O6M:T
o A:T - G  A mutation
 A=T
o Ring opening
 Alkylation destabilizes ring and breaks it open  destabilize bond
between guanine and deoxyribose (N-glycosidic bond)
Nitrogen mustards Increased risk of leukemia
Mechlorethamine with these agents
(because of DNA damage)
- R group: CH3
o CH3 group donates electrons 
increase ability of nitrogen to react
with side chains  short half-life
(reaction happens quickly)
- T1/2: 15 minutes
- Bolus IV treatment
o CANNOT be given orally
- Spontaneous reaction of aziridinium ions – not specific to tumor cells
 - Most reactive
- Treatment of lymphoma, leukemia
- Dose-limiting effect:
o Myelosuppression
 Check bone marrow before next dose is given
- Can cause hair loss (Chronic), nausea and vomiting (acute)
- Extravasation – a lot of damage and toxicity if drug escapes blood vessel
o SQ sodium thiosulfate (SH group – acts as a scavenger)
o If in blood vessel, it gets diluted in the blood. If it leaks out it stays in a specific
spot and causes a lot of damage
Melphalan
- Aromatic rings – electron
withdrawing  reduce the ability
of nitrogen to react with side
chains  form alkylating species much slower
o Can be given orally (and IV)
o Phenylalanine derivative
- Also causes bone marrow suppression, hair loss, GI toxicity (nausea and vomiting)
Chlorambucil
- Similar side effects as melphalan
o Less hair loss
- Aromatic ring
o PO/IV

Cyclophosphamide
- Nitrogen mustard
- Requires metabolic activation
(liver)
o CYP 3A4, 2C9, 2B6
- Hydroxycyclophosphamide and
aldophosphamide (Active) can be
detected in circulating blood
o Hydroxycyclophosphamide
can be inactivated into
ketocyclophosphamide
o Aldophosphamide can be
inactivated into carboxyphosphamide via aldehyde oxidase.
o Aldophosphamide can also be enzymatically broken down to acrolein and
phosphoramide mustard (Cytotoxic agents)
 Phosphoramide mustard is responsible for the anti-tumor effects
 Acrolein is responsible for bladder toxicity
o Resistance to cyclophosphamide is due to ↑ conversion to inactive metabolites
- Toxicity
 o Nausea and vomiting - acute
o Myelosuppression
o Hair loss
o Hemorrhagic cystitis
 Bladder toxicity (acrolein)
 MESNA (mercaptoethane sulfonate) – can be instilled directly into the
bladder to prevent bladder toxicity
 Hydration also helps prevent bladder toxicity
- Used to treat:
o Breast cancer
o Ovarian cancer
o Lymphomas
Iphosphamide
- More peripheral nervous system toxicity
- Better in terms of bone marrow suppression compared to cyclophosphamide
- Not used commonly

Alkyl Sulfonate (Busulfan)

- Bifunctional agent
o CH3SO3- groups can
interact with DNA that
would lead to
crosslinking
o 4/5 Carbons – greatest activity
 More/less than 5 carbons – compounds not nearly as effective
- Toxicity
o Bone marrow suppression
 When bone marrow transplant is needed, the existing bone marrow
needs to be removed  busulfan is used for bone marrow ablation
o GI toxicity – vomiting
 Treated with antiemetic compounds
o Pulmonary fibrosis
o Hepato-veno occlusive disease
 Clogging of small veins in the liver
- Used to treat CML (Chronic myelocytic leukemia)
Cisplatin [IV]
- Platinum molecule in center
o Platinum reacts with aluminum (caution with aluminum
needle - use plastic syringes and needles)
- Bifunctional agent
o Chlorine molecules can be displaced by water molecules
 formation of alkylating species
- Intra-strand and inter-strand crosslinking
 o Intra-strand crosslinking tends to occur much more rapidly compared to inter-
strand
 Bend in DNA  block progression of DNA polymerase  problems with
replication
- Toxicity
o Ototoxicity
o Nephrotoxicity
 Hydrate patient
 Treat with amifostine
 Reduce dose with existing renal disease
o Peripheral neuropathy
o Nausea and vomiting
o Myelosuppression
- Resistance due to ↑ GSH and ↑ DNA repair capacity
- Used to treat testicular cancer
Carboplatin [IV]
- 2nd generation platinum analog
- Less renal and GI toxicity
o Less hydration required (Easier for patient use)
- Still causes bone marrow toxicity
- Resistance due to ↑ DNA repair
Oxiplatin (Oxaliplatin) [IV]
- 3rd generation platinum analog (newer)
- Less resistance due to DNA repair alterations
- Toxicity
o Myelosuppression
o Peripheral neurotoxicity
o Renal toxicity (same as cisplatin)
 Hydration
 Reduce dose with existing renal disease
Mitomycin C [IV]
- Renal elimination
- Prolonged myelosuppression
o Dose limiting
- Metabolism
o CYP450 reductase converts
quinone to hydroquinone
o Methoxy group removed to
generate the intermediate
 Remaining side chains
can interact with bases
on DNA  cross-linking
on guanine
 Inter-strand crosslinking
o Produce hydrogen peroxide and hydroxyl radical
 Hydroxyl radical is very reactive  can react with macromolecules in cells
- Resistance
o Due to efflux by P-GP or ↓ activation pathways
- Extravasation can cause significant skin problems
o Can be treated with topical DMSO (dimethyl sulfoxide)
Nitrosoureas
Lomustine [PO]
- Reactive oxygen generated
o Nucleophilic attack
 if on side chain  A pathway
 if on first bond  B Pathway
- Pathway A
o Release Cl- and generate
isocyanate and diazotic
acid
o Diazotic acid can lead to
formation to carbocation
and acetaldehyde
- Pathway B
o Generate isocyanate and
positively charged chlorine
containing molecule
 Results in inter-
strand cross-linking
of DNA
- R group:
hydrophobic
ring
o CNS
penetration (more
lipophilic)
o Used to treat brain tumors
- Side effects
o Nausea and vomiting
o Myelosuppression
 Slow recovery of
bone marrow (4-6
weeks)
 Make sure bone
marrow recovers
enough before
next dose
o Delayed pulmonary
toxicity
 Monitor lung functions at higher doses
Antimetabolites
- Prevent DNA replication by mimicking an existing molecule and interfering with its
activity
Folic acid analogs
- Need folate to synthesize
DNA and proteins
- Folic acid has to be in
reduced form to
participate in reactions
- Involved in 1 carbon
transfer reactions
- Physiologic folate
o Double ring
structure +
aminobenzoic
acid+ glutamates (n – enzymes add additional glutamates – polyglutamated folic
acid)

Methotrexate (MTX)
- Antifolate
- dUMP needs to be converted into Thymidine
monophosphate (TMP) to make DNA
o Can’t synthesize DNA without
thymidine
- The difference between dUMP and TMP is a
methyl group
- The methyl group is provided by reduced
folate
o folate undergoes oxidation during
dUMP  TMP reaction
- Dihydrofolate reductase (DHFR) re-
reduces the folate to be used in another
enzymatic cycle
- Methotrexate and its polyglutamate
forms will inhibit DHFR
o Accumulation of oxidized form of
folic acid (not useful in synthesis
of TMP and DNA)
- Effective in inhibiting DHFR in all species
- De Novo purine synthesis pathway
o Reduced folic acids that donate
carbons
 o Enzymes inhibited by polyglutamated forms of methotrexate
o Accumulation of oxidized forms of folic acid
o Can’t make IMP (precursor of AMP and GMP)
o  effects on Pyrimidines and purines
- Polyglutamation
o ↓ lipid solubility
 Every time a glutamate is added a negative charge is added
 ↑ polyglutamation  ↑ negative charge  MTX gets trapped in cell 
↑ inhibition of DHFR
o Preferentially occurs in tumor cells  MTX is more selective for tumor cells vs.
non-tumor cells
- S-Phase specific
o DNA replication occurs (G1  S)
o G1: nucleotide production
 Problem with production of thymidine  slow passage of cells from G1
 S (↓ synthesis of dTTP)
 Working against effects of MTX
- Resistance
o Mutated DHFR
o DHFR gene amplification  ↑ mRNA  ↑ DHFR protein
o ↓ MTX uptake through folate transporter
o ↓ polyglutamation – can’t trap MTX in tumor cells
- Toxicity
o Myelosuppression
o Diarrhea
o Mucositis
- Primarily excreted via kidneys
o High dose  precipitation of MTX in renal tubules
 More likely in people with renal disease
- Leucovorin
o Form of reduced folate
 Inhibition of DHFR by MTX would ↓ reduced folate
o High dose MTX with leucovorin – leucovorin rescue
 Higher dose of MTX  ↑ efficacy of efficacy and ↑ risk of bone marrow
toxicity
 Follow high dose of MTX with leucovorin – timing is very important
 Give it too soon  rescue tumor cells and bone marrow cells
Pyrimidine analogs
- Disrupt pathways involved in DNA
replication
5-Flurouracil (5FU)
- Active metabolite: 5-Fluorodeoxyuridine
monophosphate (5FdUMP)
 o Needs phosphate and deoxyribose sugar
- FdUMP inhibits thymidylate synthase
- S-phase specific
o Not enough TTP  problems with DNA
synthesis
- Formation of ternary complex  more stable 
difficult to make TMP
- Leucovorin ↑ formation of ternary complex
- 5FU can be converted to 5FUTP that can be
incorporated into RNA (uridine, DNA has thymidine), can also be incorporated into DNA
 interfere with RNA processing
- Short t1/2  IV infusion
o 10-15 min
- Readily enters CNS and crosses BBB
- Metabolism
o Dihydropyrimidine dehydrogenase (DPD) – reduces double bond in 5FU and
inactivates 5FU (80% of 5FU will undergo this pathway and get deactivated)
 5% of US population have a genetic deficiency of DPD  ↑ drug available
for activation  ↑ risk of toxicity
 Determine DPD activity to give correct dose
o Only 20% of 5FU will be active
- Resistance
o ↓ activation of 5FU
o ↑ dUMP
o Altered thymydilate synthetase
- Toxicity
o Mucositis
o Diarrhea
o Myelosuppression
o Hand-foot syndrome (redness,
tingling, blisters, swelling)
o Neurotoxicity
- Used to treat a variety of solid tumors
(breast, colon, stomach, pancreatic…)
Capecitabine [PO]
- Remove side chain with carboxyesterase
(liver)
- Cytidine deaminase converts amino group
to a carbonyl group
- Get rid of ribose sugar to get rid of CH3
group and regenerate 5FU
- Normal activation pathway of 5FU
 - More specific for tumor cells because cytidine phosphorylase is increased in tumor cells
o ↑ production of 5FdUMP in tumor cells
- Toxicity – less severe than 5FU
o Myelosuppression
o Nausea and vomiting
o Mucositis
o Hand-foot syndrome
- DPD deficiency is still a problem
-
Cytarabine (AraC)[IV]
- Cytidine: OH in α configuration – difference is that OH is in β in AraC
- phosphorylate AraC with deoxycytidine kinase to
make AraCMP
o AraCMP can undergo deamination and get
deactivated
- Phosphorylate 2 more times to generate AraCTP
(Active compound)
- OR can undergo a deamination reaction (inactive
metabolite)
- Amount of phosphate generated correlates with
efficacy
- AraCTP inhibits DNA polymerase α (DNA
replication), β (DNA repair)
- Incorporate AraCTP into DNA inhibits further
extension of DNA strand
- S-phase specific
- Resistance
o ↓ deoxycytidine kinase
o ↑ cytidine deaminase
o ↑ dCTP
 dCTP competes with AraCTP
- Toxicity
o Myelosuppression
o Mucositis
o Nausea and vomiting
o Neurotoxicity (with high doses)
 Ataxia (poor muscle coordination)
Gemcitabine [IV]
- Cytidine base with deoxyribose sugar and 2 fluorine at C2.
o F interfere with ability of DNA polymerases to interact with
this molecule
- Has to undergo phosphorylation at OH group by
deoxycytidine kinase
 - Gemictabine diphosphate acts as an inhibitor of ribonucleotide reductase
o Converts ribose  deoxyribose
o  Decreased cellular dNTP (cytidine triphosphate)  can’t make DNA
- Inhibition of DNA polymerase α (DNA replication) and polymerase β (DNA repair)
- Chain termination
- Toxicity
o Myelosuppression (dose-limiting)
o GI: Nausea and vomiting
- T1/2: ~20 hours
o T1/2 AraC: 3-4hours
- Can’t be given orally – extensively metabolized in GI tract
- Effective vs. solid tumors, leukemia
Purine analogs

- Amino group attached to purine ring in GTC (only difference between the 2)
- Has to be activated – needs a ribose and phosphate

6-mercaptopurine (6MP) 6-thioguanine (6TG)

- Ribose and phosphate added in 1 step by

HGPRT (Hypoxanthine-Guanine
phosphoribosyl transferase)
o Monophosphate is the active
metabolite – Thiopurine
ribonucleotide
- TPMT [Thiopurine methyl transferase]
(methylation)
o Methyl group is donated by SAM
- Methylated sulfur  inactivated
molecule
- Amount of active metabolite will be
determined by how much the reaction
goes through HGPRT vs. TPMT
- TPMT can methylate the active
monophosphate  active metabolite – S-methyl thiopurine ribonucleotide
 - Xanthine oxidase (inactivating metabolite) –inhibited by allopurinol (used to treat gout)
o Inactivates the thiopurine prodrug and the active metabolite
o ↓ dose by 50% if used with allopurinol
- MOA
o Incorporation into DNA – convert the monophosphate by 2 more
phosphorylation
 More relevant for 6TGTP  lack of continued elongation  apoptosis
o Purine production: PRPP  IMP  AMP + GMP
 IMP dehydrogenase converts IMP  GMP
 Adenylosuccinate synthetase converts IMP  AMP
 6MP Inhibits IMP dehydrogenase and adenylosuccinate synthetase
- Side effects
o Myelosuppression
o Hepatotoxicity at higher doses (6TG)
- Resistance
o Lack of HGPRT
- TPMT polymorphism
o +/+ (90% of US population)
o +/- (1-10%) – low activity
o -/- (0.3%) – no activity
 Lack of TPMT  ↑ Activated compound  ↑ efficacy + ↑ bone marrow
toxicity
 ↓ 90% of normal dose to avoid toxicity
o  Need Genetic testing to determine amount of TPMT
Cladribine [IV]
- Purine ring with Cl group
o Cl- blocks deamination by adenosine deaminase
o  accumulation of active metabolite  immunosuppressive
effects
 Immune cells are impacted because they rely on the De
Novo purine synthesis pathways
 Immune cells are not able to replicate DNA
 ↓ CD4+, 8+  lack of proper immune system function
- Has to undergo phosphorylation by deoxycytidine kinase
o Subsequent phosphorylation to triphosphate that could be incorporated DNA 
inhibit DNA polymerase α and β  accumulation of DNA strand breaks
- Resistance
o Lack of deoxycytidine kinase – can’t generate active metabolite (1st
phosphorylation)
- Infuse over 1 week
Tubulin inhibitors
Vincristine/Vinblastine [IV]
- Acetyl group can undergo deacetylation
 active metabolite
- If OH groups are modified  inactive
compound
- MOA
o Interfere with microtubule
function
o Tubulin  microtubules
mitosis
o Both bind to tubulin and block
tubulin polymerization into
microtubule  cell can’t progress through M phase (M-phase specific)
 Mitotic arrest
- Vincristine has a much longer t1/2
o Metabolized slower
- Both undergo extensive CYP metabolism
- Excreted via bile
- Dose modified if liver disease present
- Resistance
o Efflux pump (P-GP)
- Vinblastine toxicity
o Myelosuppression (Bone marrow)
o Hair loss
o Nausea and vomiting
- Vincristine toxicity
o Neurological toxicity
 Numbness
 Muscular weakness
 Tingling
 Motor dysfunction
 Foot Drop syndrome
 Can’t hold ankle up
o Mild myelosuppression
o Severe constipation
Paclitaxel/Docetaxel [IV]

- Both bind to β-tubulin (already incorporated

in microtubules) – block depolymerization
(Disassembly) of microtubules  mitotic
arrest – M-phase specific
- R1/R2
 - Poorly soluble in aqueous solutions
o Cremaphor ↑ water solubility  could cause hypersensitivity reaction
 Pre-treat with dexamethasone or anti-histamines (diphenhydramine)
- Extensive P450 metabolism
o ↓ dose with liver disease
- Resistance
o P-GP efflux pump
- Toxicity
o Myelosuppression
o Peripheral neuropathy
o Hypersensitivity reactions
Abraxane
- Reformulation of paclitaxel
- Nano-particle technology
- Albumin bound paclitaxel
o No Cremophor associated  Lack of hypersensitivity reactions

Ixabepilone
- Microtubule inhibitor
- Stabilizes microtubules
- Effective against resistant tumors (P-GP or mutated β-tumulin – Paclitaxel resistance)
- Toxicity
o Myelosuppression
o Hypersensitivity
o Peripheral neuropathy
 More sensory than motor
Eribulin
- Effective against Paclitaxel - resistant tumors (P-GP)
- Binds to ends of existing microtubules  apoptosis
- Toxicity
o Myelosuppression
o Hair loss
o Peripheral neuropathy

Topoisomerase inhibitor
Etoposide
- Topoisomerase II inhibition
o Responsible for managing supercoiling within DNA superhelix
 Has to cut both strands of DNA helix
o Unable to seal the breaks in DNA  Accumulation of strand breaks
- Forms ternary complex with DNA and Topo II
- Resistance
o Alterations in Topo II
 o P-GP
- Toxicity
o Myelosuppression
o Hair loss
o Hypersensitivity (ingredients in formulation)
o ↑ risk of leukemia several years after treatment
- Excreted via renal and biliary secretion
- Decrease dose with renal disease

Irinotecan [IV]
- Inhibition of Topoisomerase I
o Only cuts 1 strand of DNA
 Cuts can’t be ligated  single and double strand breaks in DNA 
trouble with DNA replication  apoptosis
- S-phase specific
- Irinotecan (parent) is inactive
o Removal of bis-piperidine rings  SN-
38 (active metabolite – responsible for
interaction with Topo I)
 OH group at site of reaction
o Can interact with CYP 3A4
 Generates inactive metabolites
 Glucuronidation of SN-38
(UGT1A1)
  SN-38-UGT – inactive
metabolite
- Biliary secretion (SN-38 and SN-38-UGT)
- ↓ dose with renal disease
- Resistance
o Lack of carboxylesterase that removes
bis-piperidine side chain
- Toxicity
o GI tract – severe acute or delayed (2-
10 days after treatment) diarrhea
 Due to accumulation of SN-38
 Treated with loperamide
o Myelosuppression
- Polymorphism associated with UGT1A1
o ↓ glucuronidation  Gilbert Syndrome (10-15% of population)  ↓ dose to
avoid toxicity
o Genetic testing
Anthracycline
Doxorubicin/Daunorubicin

- Quinone structure
o Can interact with iron – Fe-dependent formation of oxygen radicals  can cause
damage to DNA and macromolecules within cell
- Intercalation into DNA helix
o Planar molecule – can slip in between base pairs and disrupt ability of DNA to
serve as a template for DNA replication and RNA synthesis
- ↓ Topo II
o Broken DNA strands
- Toxicity
o Most toxicity seen during S-phase – problems with DNA replication
o Myelosuppression
o Hair loss
o Mucositis
o Cardiomyopathy
 Generation of ROS in heart tissue
 Enzymes (catalase) responsible for scavenging and converting ROS
to non-reactive properties and heart tissue has less of these
enzymes - ↓ protection
o Red/orange urine
- Extensive hepatic P450 metabolism
- Extensive biliary secretion
-  reduce dose with liver disease
- Extravasation
o Dexrazoxane (Fe chelator)- take away iron and prevent damage from occurring
Bleomycin [IV]
- DNA binding
- Fe binding
o Generates oxygen radicals 
DNA strand breaks
(single/double)
- Chromosomal damage
- Accumulation of cells in G2 phase
(can’t move into mitosis)
- Bleomycin Hydrase
o Removes amino group and
generates a carboxyl group
 inactive metabolite  ↓
affinity for binding to DNA
- Tumors with ↑ bleomycin hydrase
are resistant to bleomycin
- Metabolized by bleomycin
hydrolase
- Renal excretion
o ↓ dose with kidney disease
- Toxicity – corelated with amount of
bleomycin hydrolase activity within
these tissue (↓ in lungs and skin  ↑ active drug  ↑ ROS)
o Cutaneous
o Pulmonary
 Dose-limiting
 Incidence increases with:
 Age (>70 y/o),
 Existing pulmonary disease
 ↑ Cumulative dosing
 Previous chest X-rays (irradiation)
 Monitor lung function with bleomycin use
o Hyperthermia