Nursing Pharmacology: Cancer Chemotherapy: Drug Classification and Mechanism of Action
Polyfunctional alkylating agents
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)
Pharmacological Effects: Polyfunctional Alkylating Drugs
Injection site damage (vesicant effects) and systemic toxicity.
Primarily affecting rapidly dividing cells
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.
Cyclophosphamide cytotoxicity depends on activation by microsomal enzyme system.
Hepatic microsomal P450 mixed-function oxidase catalyzes conversion of cyclophosphamide to the active forms:
Major Toxicity: bone marrow suppression
Dose-related suppression of myelopoiesis: primary effects on
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
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
Minimal bone marrow suppression
Effective in insulin-secreting islet cell pancreatic carcinoma and sometimes in non-Hodgkin's lymphoma
Other Alkylating Drugs
Active in Hodgkin's disease (combination therapy)
Teratogenic, mutagenic, leukemogenic.
Nausea, vomiting, myelosuppression
Soft tissue sarcoma
Synthetic drug; requires activation by liver microsomal system.
Nausea, vomiting, myelosuppression
Alkylating agent-resistant: ovarian carcinoma
Activated by biotransformation (demethylation)
Nausea, vomiting, central and peripheral nervous system neuropathies.
Relatively mild myelosuppressive effects
In combination with bleomycin and vinblastine: curative treatment for nonseminomatous testicular cancer
Carboplatin (less GI and renal toxicity; with myelosuppressive toxicity): alternative to cisplatin
Inhibits DNA synthesis; cross-linking; guanine N7 site
Platinum compounds: synergistic with other anticancer agents
Major acute effect: nausea, vomiting
Relatively little bone marrow effects
Significant renal dysfunction (minimized by adequate hydration/diuretics)
Acoustic nerve dysfunction
IV mechlorethamine, cyclophosphamide, carmustine: Nausea and Vomiting (common)
Oral cyclophosphamide: Nausea and Vomiting (less frequently)
Most Important Toxic Effect:Bone marrow suppression, leukopenia, thrombocytopenia
Secondary to myelosuppression --
Cyclophosphamide (Cytoxan):alopecia, hemorrhagic cystitis (may be avoided by adequate hydration)
Salmon, S. E. and Sartorelli, A. C. Cancer Chemotherapy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 881-911.