- Common Structural Features:
- bis(chloroethyl)amine
- ethylenimine
- nitrosoureas
- Not cell-cycle specific: Cells most
susceptible in late G1 and S phase-- Blocks in G2
Most useful agents:
- Cyclophosphamide (Cytoxan)
- Mechlorethamine
- Melphalan (Alkeran)
- Chlorambucil (Leukeran)
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Secondary agents
- Thiopeta (Thioplex)
- Busulfan (Myleran)
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Major nitrosoureas:
- Carmustine (BCNU)
- Lomustine (CCNU)
- Semustine (methyl CCNU)
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Polyfunctional Alkylating Drugs: Mechanism of
Action:
- Alkyl
group transfer
- Major
interaction: Alkylation of DNA
- Primary DNA
alkylation site: N7 position of
guanine (other sites as well)
- interaction may
involve single strands or both
strands (cross linking, due to
bifunctional [2 reactive centers]
characteristics)
- Other interactions: these
drugs react with carboxyl, sulfhydryl,
amino, hydroxyl, and phosphate groups of
other cellular constituents
- These drugs usually form a
reactive intermediate -- ethyleneimonium
ion
Polyfunctional Alkylating Drug Resistance
- Increased ability to repair DNA
defects
- Decreased cellular permeability to
the drug
- Increased glutathione synthesis
- inactivates alkylating
agents through conjugation reactions
(catalyzed by glutathione S-transferase)
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Pharmacological Effects: Polyfunctional
Alkylating Drugs
- Injection site damage (vesicant effects)
and systemic toxicity.
- Toxicity:
- dose related
- primarily
affecting rapidly dividing cells
- bone marrow
- GI tract
- nausea
and vomiting within
less than an hour-- with
mechlorethamine,
carmustine (BCNU) or
cyclophosphamide
- Emetic
effects: CNS
- reduced
by pre-treatment with phenothiazines
or cannabinoids.
- gonads
- Cyclophosphamide
cytotoxicity depends on activation by
microsomal enzyme system.
- Hepatic microsomal
P450 mixed-function oxidase
catalyzes conversion of
cyclophosphamide to the active
forms:
- 4-hydroxycyclophosphamide
- aldophosphamide
- Major Toxicity: bone marrow
suppression
- dose-related
suppression of myelopoiesis:
primary effects on
- megakaryocytes
- platelets
- granulocytes
- Bone
marrow suppression is worse when
alkylating agents are combined
with other myelosuppressive drugs
and/or radiation (dose
reduction required)
- If bone
marrow suppression is severe,
treatment may have to be
suspended and then re--initiated
upon hematopoietic recovery.
- Long-term
consequences of alkylating agent
treatment include:
- ovarian
failure (common)
- testicular
failure (common)
- acute
leukemia (rare)
- Oral Route of
Administration:cyclophosphamide (Cytoxan),
melphalan (Alkeran), chlorambucil (Leukeran),
busulfan (Myleran), lomustine (CCNU,CeeNU)
- Cyclophosphamide (Cytoxan): most useful
alkylating agent at present.
- Busulfan (Myleran):
specificity for granulocytes -- chronic
myelogenous leukemia
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- Nitrosoureas:
- not cross
reactive ( with respect to tumor
resistance) with other alkylating drugs.
- Nonenzymatic by
transformation required to activate
compounds.
- Highly lipid-
soluble-- crosses the blood-brain barrier
(BBB)
- useful in treating
brain tumors
- Act by cross-linking: DNA
alkylation
- More effective against
cells in plateau phase than cells in
exponential growth phase
- Major route of
elimination:urinary excretion
- Steptozocin:
- sugar-containing
nitrosourea
- minimal bone
marrow suppression
- effective in
insulin-secreting islet cell
pancreatic carcinoma and
sometimes in non-Hodgkin's
lymphoma
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