KU PPB 423 Lesson 3 - Alkylating Agents

ALYKATING
AGENTS &
PLATINUM
ANALOGS
Lesson 2
PPB 423 – Neoplastic
Diseases & Anticancer
Drugs
KU – BPHARM 4,
TRIMESTER II
Dr. Hilda Nderitu
15th January 2021
Objectives
•Describe & discuss the pharmacological
properties of:
•Alkylating agents
•Platinum analogs
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ALKYLATING AGENTS

Alkylating agents - groups
Nitrogen mustards
Nitrosoureas
Alkyl sulfonates
Triazenes
Ethyleneimines
Methylhydrazines
Classic alkylating agents
Nitrogen mustards Nitrosoureas Alkyl
sulfonates
• Mechlorethamine • Lomustine • Busulphan
• Cyclophosphamide (CCNU)
• Ifosfamide • Streptozocin
• Chlorambucil • Carmustine
• Melphalan (BCNU)
• Estramustine

Non-classic alkylating agents
• Dacarbazine
Triazenes • Temozolomide
• Thiotepa
Ethyleneimines • Tretamine/triethylenemelamine
• Altretamine
• Procarbazine
Methylhydrazines • Bendamustine
Mode of action: Alkylating agents
• Through transfer of their alkyl groups to various cellular
constituents
• Occurs via intramolecular cyclization to form an
ethyleneimonium ion that may directly or through
formation of a carbonium ion transfer an alkyl group to a
cellular constituent
• Cell death – occurs through alkylation of DNA within the
nucleus
• Also react chemically with sulfhydryl, amino, hydroxyl,
carboxyl & phosphate groups of other cellular nucleophiles

ethyleneimonium ion
Carbonium ion
Mode of action:Alkylating agents -
ii
•DNA alkylation sites
•N7 position of guanine – major site
•N1 & N3 of adenine
•N3 of cytosine
•O6 of guanine
•Phosphate atoms & proteins associated
with DNA

Mode of action: Alkylating agents
- iii
•Alkylation of guanine results in:
• Miscoding through abnormal base pairing with thymine
• Depurination by excision of guanine residues
• Leads to DNA strand breakage through scission of the sugar-
phosphate backbone of DNA
•Interactions occur on single strands or both strands of
DNA through cross-linking
• Because most major alkylating agents are bifunctional,
with 2 reactive groups

Mode of action: Alkylating agents -
iv
•Cross-linking of DNA results in:
• Abnormal replication & transcription
• Block at G2 phase
• Subsequent apoptotic cell death

Mode of action: Alkylating agents - v

Mode of action: Alkylating agents - vi
•2nd mechanism
•Occurs with Nitrosoureas
•Involves carbamoylation of lysine residues
of proteins through formation of
isocyanates
•Replicating cells
•Most susceptible in late G1 & S phases of
the cell cycle

Adverse effects: group specific
•Dose related, include:
•Bone marrow suppression/myelosuppression
•GIT disturbances – nausea, vomiting
•Damage of tissues at site of administration
•Systemic toxicity
•Depression of gametogenesis with prolonged
use – esp men, leading to sterility
•é risk of acute non-lymphocytic leukaemia &
other malignancies with prolonged use

NITROGEN MUSTARDS

Cyclophosphamide: PD properties
1. Alkylating agents
2. Immunosuppressant
•Has an inhibitory effect on B-cells,
CD4+ T-cells & to a lesser extent on
CD8+-T-cells
•Also assumed to have inhibitory effect
on the suppressor that regulate the
IgG2 class of antibodies
Cyclophosphamide: PK properties
Absorption • Rapidly & almost completely absorbed from parenteral sites
• High oral bioavailability
Distribution • < 20% of cyclophosphamide is bound to plasma proteins
• Protein binding of metabolites of cyclophosphamide is higher but < 70%
• Excreted in CSF & breast milk
• Cyclophosphamide & metabolites can pass through placenta
Metabolism • Inactive in it’s parent form
• Activated in the liver to the active metabolites 4-hydroxy-
cyclophosphamide & aldofosfamide by CYP450 enzymes (CYP2A6, 2B6,
2C9, 2C19 & 3A4) CYP2B6 exhibits highest 4-hydroxylase activity
• Detoxification by glutathione-S-transferases (GSTA1, GSTP1) & alcohol
dehydrogenase (ALDH1, ALDH3)
• 2 – 4 hours after administration of cyclophosphamide, the plasma
concentrations of the active metabolites are maximal, after which a rapid
↓ of plasma concentrations takes place
Elimination • Plasma t ½ of cyclophosphamide: 4 – 8 hours
• Plasma t ½ of active metabolites: not known
• Cyclophosphamide & its metabolites are primarily excreted by the
kidneys
Metabolism of cyclophosphamide
Haemorrhagic
cystitis

Cyclophosphamide: clinical uses
•Breast cancer
•Ovarian cancer
•Non-Hodgkin’s lymphoma
•CLL
•Soft tissue sarcoma
•Neuroblastoma
•Wilms’ tumor
•Rhabdomyosarcoma
•Routes of admn: PO, IV bolus, IV infusion

Cyclophosphamide: adverse
effects
•Acute toxicity - nausea & vomitting
•Delayed toxicity
•Bone marrow suppression
•Haemorrhagic cystitis
•Caused by acrolein
•Ameliorated by
• é fluid uptake
• Use of sulfhydryl donors, such as N-acetylcysteine
or Mesna (sodium-2-mercaptoethane sulfonate)
• Interact with acrolein to form a non-toxic cpd
Other Nitrogen Uses Acute Delayed toxicity
mustards toxicity
Mechlorethamine • Hodgkin’s Nausea • Moderate
• Non- & depression of
Hodgkin’s vomiting peripheral blood
lymphoma count
Chlorambucil • CLL Nausea • Excessive dose -
• Non- & severe bone
Hodgkin’s vomiting marrow
lymphoma depression with
leukopenia,
Melphalan • Multiple Nausea
thrombocytopenia
myeloma &
& bleeding
• Breast vomiting
cancer
• Ovarian
Friday, January 15, 2021 cancer Dr. Nderitu H 21
Other nitrogen mustards
•Ifosfamide
•Adverse effect - haemorrhagic cystitis (see
cyclophosphamide)
•Estramustine
•Combination of chlormethine (mustine) &
oestrogen
•Both cytotoxic & hormonal action
•Uses
• Prostate cancer

NITROSOUREAS

Nitrosoureas: mode of action
•Requires biotransformation in the body
to active form
•Via non-enzymatic decomposition to
metabolites with alkylating &
carbamoylating activities
•Cytotoxic effect
•Through alkylation on O6 position of
guanine leading to G-C crosslinks in DNA

Nitrosoureas: PK properties
•Highly lipid soluble
•Cross blood brain barrier
•Therefore effective in brain tumours
•Excretion – via urine

Nitrosoureas
Drug Uses Acute Delayed toxicity
toxicity
Lomustine Brain cancer Nausea & • Myelosuppression
vomiting • Interstitial lung
disease (rare)
Carmustine Brain cancer Nausea & • Interstitial nephritis
Hodgkin’s & vomitting (rare)
non-Hodgkin’s
lymphoma
Streptozocin Insulin-secreting Nausea & • Minimal bone
islet cell vomiting marrow suppression
carcinoma of • Nephrotoxicity
the pancreas

AKYLSULPHONATES

Busulfan
•PD properties
•Bifunctional alkylating agent
•Effects
• Low dosage – depresses formation of granulocytes
& platelets
• High dosage – depresses red cells formation
•Clinical uses
•Chronic myelogenous leukemia (CML)
•Admn: P.O, IV infusion
Busulfan: PK Properties
Absorption Oral bioavailability: 47 – 100%
Distribution • In high doses enters CSF
• Binds to blood cells, plasma proteins & albumin
Metabolism • Metabolised through reaction with glutathione, which
occurs via the liver & is mediated by glutathione-S-
transferase
• Metabolites - 3-hydroxysulpholane, tetrahydrothiophene
1-oxide & sulpholane
Elimination • Metabolites excreted in urine
• Mean elimination t ½:2.3 - 2.8 hours – elimination t ½ ↓
upon repeat dosing suggesting that busulfan potentially
↑ its own metabolism
• Clearance: 2.4 - 2.6 ml/min/kg.
• Very little (1 - 2 %) busulfan is excreted unchanged in
urine
Busulfan: toxicities
Acute toxicity Delayed toxicity
• Nausea & üSkin pigmentation
vomiting üPulmonary fibrosis
üAdrenal insufficiency
üSelective effect on bone
marrow

Non-classic alkylating agents

Procarbazine
•Mode of Action
•Inhibits DNA, RNA & protein synthesis
•Prolongs interphase
•Oxidative metabolism by microsomal
enzymes to generate active metabolites
responsible for DNA strand scission
•Higher carcinogenic potential than that of
most other alkylating agents
Procarbazine: PK Properties
Absorption • Readily absorbed from GIT
Distribution • Peak plasma levels: 0.5-1 hour after PO administration
• Procarbazine quickly equilibrates between the blood and
cerebrospinal fluid (CSF)
• Peak CSF levels achieved 30-90 minutes after oral
administration
Metabolism • Rapidly metabolised, the primary circulating metabolite is the
azo derivative while the major urinary metabolite has been
shown to be N-isopropyl-terephthalamic acid
Elimination • Plasma t ½: 10 minutes
• Approx. 5% of procarbazine is excreted unchanged in urine
• Remainder is oxidised to N-isopropylterephthalamic acid &
excreted in urine, up to about 70% of a dose being excreted
in 24 hours
• Some of the drug is excreted as carbon dioxide & methane
via the lungs
Procarbazine: Clinical uses
•Clinical uses
•Hodgkin’s
•Non-Hodgkin’s lymphoma
•Brain tumours
•Routes of administration
•P.O

Procarbazine: toxicities
CNS depression • Myelosuppression
• Hypersensitivity reactions
– may require stopping
treatment

Procarbazine – drug interactions
•Exacerbates effects of CNS depressants
•Weak monoamine oxidase inhibitor (via it’s
metabolite)
•Causes hypertension if given with certain
sympathomimetic agents
•Causes disulfiram-like actions with
alcohol

Dacarbazine
•Mode of Action
•Pro drug
•Metabolic activation in the liver by
oxidative N-demethylation to
monomethyl derivative
•Monomethyl derivative spontaneously
decomposes to diazomethane, which
generates a methyl carbonium ion that
causes cytotoxic effect
Dacarbazine: PK Properties
Distribution • After IV administration dacarbazine is quickly distributed
into tissue
• Plasma protein binding is 5 %
• Kinetics in plasma are biphasic;
• Initial (distribution) t ½: 20 minutes
• Terminal t ½: 0.5 – 3.5 hours
Metabolism • Dacarbazine is inactive until metabolised in the liver by
CYP450 to form the reactive N-demethylated species
HMMTIC & MTIC
• Catalysed by CYP1A1, CYP1A2 & CYP2E1
• MTIC is further metabolised to 5-aminoimidazole-4-
carboxamide (AIC)
• Metabolic inactivation mainly in the liver by both
hydroxylation & demethylation
Elimination • Approx. 20 – 50 % of the drug is excreted unhcanged by
the kidney via renal tubular secretion
Dacarbazine: Clinical uses
• Clinical uses
• Hodgkin’s lymphoma
• Malignant Melanoma
• Soft tissue sarcoma
•Administration
•IV infusion
•Caution
•Potent vesicant
• Avoid extravasation during drug administration

Dacarbazine: toxicities
Acute Toxicity Chronic toxicity
Nausea & • Myelosuppression
vomiting • Central nervous system toxicity with:
• Neuropathy
• Ataxia
• Lethargy
• Confusion

Table 1: Non-classic alkylating agents
Drug Uses Acute toxicity Delayed toxicity
Temozolomide • Brain • Nausea & • Myelosuppression
cancer vomiting • Mild elevation in
• Melanoma • Headache liver function tests
• Fatigue • Photosensitivity
Altretamine Ovarian • Nausea & • Myelosuppression
cancer vomiting • Peripheral
neuropathy
• Flu-like syndrome

Table 2: Non - classic alkylating agents
Uses Acute Delayed toxicity
Drug toxicity
• Chronic
lymphocytic Nausea
• Moderate
Bendamustine leukemia &
depression of
• Non- vomiting
peripheral blood
Hodgkin’s
count
lymphoma
• Excessive dose
• Breast cancer Ø Severe bone
• Ovarian marrow depression
Thiotepa Nausea with leukopenia,
cancer
& thrombocytopenia
• Superficial
vomiting & bleeding
bladder
Friday, January 15, 2021
cancer Dr. Nderitu H 42
PLATINUM ANALOGS

Platinum analogs
Cisplatin – 1st generation
Carboplatin – 2nd generation
Oxaliplatin – 3rd generation

Mode of action
•Similar to alkylating agents
•May also be referred to as alkylating
agents
•However, they do not form carbonium ion
intermediates, but covalently bind to
nucleophillic sites on DNA
•Primary binding site - N7 position of
guanine
Mode of action - ii
•Bind DNA through:
•Formation of intra strand & inter strand
cross-links
•Leading to inhibition of DNA synthesis &
function
•May also covalently interact with N3
position of adenine & O6 position of
cytosine

Mode of action - iii
•Also bind to cytoplasmic & nuclear proteins
to cause cytotoxic & antitumour effects
•Kill tumour cells in all stages of cell cycle
•Synergistic effect with other anticancer
drugs such as:
•Alkylating agents
•Fluoropyrimidines
•Taxanes
1. Cisplatin
• Anorganic substance containing a heavy metal [cis-
diamminedichloroplatinum(II)]
• Mechanism of action
• Inhibits DNA synthesis by realising transverse connections
within & between the DNA strands
• Protein & RNA synthesis is inhibited to a lesser extent
• Cytotoxicity caused by binding all DNA bases, with a
preference for the N-7 position of guanine & adenosine
• Other antineoplastic process include:
• Immunosuppressive
• Radiosensitising
• Antibacterial
• Not cell cycle specific
Cisplatin: PK properties
Distribution • After IV administration, cisplatin is rapidly
distributed among all tissues
• Following cisplatin doses of 20 -120 mg/m2, the
concentrations of platinum are highest in liver,
prostate & kidney, somewhat lower in bladder,
muscles, testicle, pancreas & spleen & lowest in
bowel, adrenal, heart, lung, cerebrum &
cerebellum
• > 90% of total plasma cisplatin is protein
bound after 2 hours following administration
Protein-bound part is not active
Metabolism • Converted by a non-enzymatic process into 1 or
more metabolites

Cisplatin: PK properties - ii
Elimination • Elimination from plasma in 2 phases after IV bolus injection
of 50-100 mg/m2 of cisplatin.
• t ½ (distribution): 10-60 minutes
• t ½ (terminal): approximately 2-5 days
• Extensively cleared by the kidneys & excreted in the urine
• Considerable protein binding of total platinum contents
results in an extended or incomplete excretion phase
with cumulative urine secretion ranging from 27 - 45%
of the administered dose in a period from 84 -120
hours
• Extended infusion results in urine secretion of a larger
part of the dose
• Renal dysfunction ↑plasma t ½ - need for dose
modification
• Minimal faecal excretion
• Small amounts of platinum can be traced in gallbladder &
the large intestine
Cisplatin: Clinical uses
• Non-small cell lung cancer
• Small cell lung cancer
• Breast cancer
• Bladder cancer
• Cholangiocarcinoma
• Gastroesophageal cancer
• Head & neck cancer
• Ovarian cancer
• Germ cell cancer
• Administration: slow I.V injection or infusion

Cisplatin: toxicities
Nausea & vomiting • Nephrotoxicity
• Very Severe • Very nephrotoxic
• Px - 5-HT3 receptor • Strict regimens of hydration &
antagonist e.g. diuresis given
ondansetron • Peripheral sensory neuropathy
• Ototoxicity
• Tinnitus & hearing loss in high
frequency range
• Nerve dysfunction
• Hyperuricaemia
• Anaphylactic reactions
2. Carboplatin: PK properties
Absorption • After a 1-hour infusion (20-520mg/m2), plasma levels of total
platinum & free platinum decay biphasically following 1st order
kinetics
• For free platinum, the initial phase t ½: ~ 90 minutes & the later
phase t½: ~ 6 hours
• All free platinum is in the form of carboplatin in the 1st 4 hours
after administration
Distribution • Protein binding reaches 85-89% within 24 hours of
administration, although during the first 4 hours, only up to 29%
of the dose is protein bound
• Patients with poor renal function may require dosage adjustments
due to altered pharmacokinetics of carboplatin.
Elimination • Excreted primarily by glomerular filtration in urine
• Most of the drug is excreted within the first 6 hours
• Approximately 32% of a given dose of carboplatin is excreted
unchanged

Carboplatin: Clinical uses
• Non-small cell & small cell lung cancer
• Breast cancer Bladder cancer
• Head & neck
cancer
• Ovarian cancer
•Administration: IV infusion
•Easier to administer as IV hydration is not required
for carboplatin therapy
•Hence it has replaced cisplatin in various
combination chemotherapy regimens
Carboplatin: Toxicities
Nausea & vomiting • Myelosuppression
• Main dose-limiting toxicity
• Rarely peripheral neuropathy
• Renal toxicity
• Exhibits significantly less renal
toxicity
• Hepatic dysfunction
• Exhibits significantly less GI
toxicity

3. Oxaliplatin: PK properties
Absorption • At the end of a 2-hour infusion, 15 % of
administered drug is present in systemic circulation,
the remaining 85 % being rapidly distributed into
tissues or eliminated in urine
Distribution • Irreversible binding to red blood cells & plasma,
results in t ½ in these matrices that are close to the
natural turnover of red blood cells & serum albumin
Metabolism • Undergoes extensive non-enzymatic
biotransformation
Elimination • Predominantly excreted in urine, with clearance
mainly in the 48 hours following administration

Oxaliplatin: Clinical uses
•Colorectal cancer
•Gastroesophageal cancer
•Pancreatic cancer
•Administration: IV infusion

Oxaliplatin: Toxicities
Acute toxicity
• Nausea & vomiting
• Laryngopharyngeal dysesthesias *
* uncomfortable persistent sensation in the area of the laryngopharynx
Delayed toxicity
• Neurotoxicity – manifests as peripheral sensory neuropathy
• Main dose-limiting toxicity
• 2 forms of neurotoxicity
• Acute form - Triggered & worsened by exposure to cold
• Chronic form
• Dependent on cumulative dose of drug administered
• Tends to be reversible, in contrast to cisplatin-induced neurotoxicity
• Myelosuppression
• Diarrhoea


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ALYKATING

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•Routes of admn: PO, IV bolus, IV infusion

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Cisplatin – 1st generation

Carboplatin – 2nd generation

Oxaliplatin – 3rd generation

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