• Polyfunctional alkylating agents

  • Mechanism of Action

  • Drug Resistance

  • Pharmacological Effects

  • Nitrosoureas

• Other Alkylating Drugs

  • Procarbazine (Matulane)

  • Dacarbazine (DTIC)

  • Altretamine (Hexalen)

  • Cisplatin cisplatin (Platinol)

• Alkylating Agent Toxicity

Antimetabolites

• Methotrexate

• Purine antagonists

  • Mercaptopurine (6-MP)

  • Thioguanine (6-TG)

  • Fludarabine Phosphate

  • Cladribine (Leustatin)

  • Pentostatin (Nipent)

• Pyrimidine antagonists

  • Fluorouracil (5-FU)

  • Cytarabine (ARA-C)

  • Azacitidine

• Plant alkaloids

  • Vinblastine (Velban)

  • Vincristine (Oncovin)

  • Etoposide (VP-16,VePe-sid)

  • Teniposide (Vumon)

  • Topotecan (Hycamtin)

  • Irinotecan (Camptosar)

  • Paclitaxel (Taxol)

  • Docetaxel (Taxotere)

• Antibiotics

  • Anthracyclines

    • Doxorubicin (Adriamycin, Rubex, Doxil)

    • Daunorubicin (DaunoXome)

  • Dactinomycin (Cosmegen)

  • Idarubincin (Idamycin)

  • Plicamycin (Mithramycin)

  • Mitomycin (Mutamycin)

  • Bleomycin (Blenoxane)

• Hormonal agents

  • Introduction

  • Tamoxifen (Nolvadex)

  • Flutamide (Eulexin)

  • Gonadotropin-Releasing Hormone Agonists

    • (Leuprolide and Goserelin (Zoladex))

  • Aromatase Inhibitors

    • Aminoglutethimide

    • Anastrozole (Arimidex)

• Miscellaneous anticancer drugs

  • Amsacrine

  • Hydroxyurea (Hydrea)

  • Asparaginase (El-spar)

  • Mitoxantrone (Novantrone)

  • Mitotane

  • Retinoic Acid Derivatives

  • Bone Marrow Growth Factors

  • Amifostine

• Common Structural Features:

  • Bis(chloroethyl)amine

  • Ethylenimine

  • Nitrosoureas

  Not cell-cycle specific: Cells most susceptible in late G1 and S phase-- Blocks in G2

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.

• 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

• 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

• Procarbazine (Matulane)

  • Methylhydrazine derivative

  • Active in Hodgkin's disease (combination therapy)

  • Teratogenic, mutagenic, leukemogenic.

  • Side effects:

    • Nausea, vomiting, myelosuppression

    • Hemolytic anemia

    • Pulmonary effects

• Dacarbazine (DTIC)

  • Clinical use:

    • Melanoma

    • Hodgkin's disease

    • Soft tissue sarcoma

  • Synthetic drug; requires activation by liver microsomal system.

  • Parenteral administration

  • Side effects:

    • Nausea, vomiting, myelosuppression

• Altretamine (Hexalen)

  • Clinical use:

    • Alkylating agent-resistant: ovarian carcinoma

  • Activated by biotransformation (demethylation)

  •  Side effects:

    • Nausea, vomiting, central and peripheral nervous system neuropathies.

    • Relatively mild myelosuppressive effects.

• Cisplatin (Platinol)

  • Clinical use:

    • Genitourinary cancers

      • Testicular

      • Ovarian

      • Bladder

    • 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

  • Site effects:

    • 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 --

    • Severe infection

    • Septicemia

  • Hemorrhage

• Cyclophosphamide (Cytoxan):alopecia, hemorrhagic cystitis (may be avoided by adequate hydration)