Microtubule inhibitors

Microtubules Inhibitors These drugs disrupt microtubules, which are structures that pull the cell apart when it divides are derived from natural substances such as plant alkaloids

ANTIMICROTUBULE AGENTS

Microtubules Inhibitors CCS Vinca alkaloids Vinblastine Vincristine Taxanes Paclitaxel Docetaxel Podophyllotoxine

Vinblastine and Vincristine Both drugs are cell cycle-specific because they block mitosis in metaphase They bind to the microtubular protein, tubulin and thus preventing the cell from making the spindles This results in arrest of mitosis at metaphase

Therapeutic Uses Adverse Effects: Vinblastine is used in testicular carcinoma, Hodgkin’s disease Vincristine is used in the treatment of acute leukemia in children, Wilm’s tumor, and Hodgkin’s and non-Hodgkin’s lymphomas Adverse Effects: Common adverse effects for both drugs include cellulitis or phlebitis if the drugs extra vasate during injection Nausea, vomiting, diarrhea, and alopecia

Toxicity of Vinblastine & Vincristine Myelo-supression Peripheral neuropathy: Depressed deep tendon reflex, paresthesia, foot drop Vincristine NOT myelosuppressant

Taxanes Interferes with cell division by keeping the spindles from being broken down (freeze) Paclitaxel (Taxol) shows good activity against metastatic breast cancer and advanced ovarian cancer Side effects; neutropenia ‼, peripheral neuropathy Filgrastim ( granulocyte colony stimulating factor)

V. Miscellaneous Anticancer Agents

V- Miscellaneous Agents L-Asparaginase Hydroxyurea Mitotane Retenoic acid derivatives Interferon

Asparagine is amino acid required for protein synthesis) L- Asparaginase Asparagine is amino acid required for protein synthesis) Neoplastic cells require an external source of asparagine (from the plasma) because of their limited capacity to make sufficient asparagine to support growth

L-Asparaginase L-asparaginase Asparagine aspartic acid +Ammonia L-asparaginase hydrolyzes serum asparagine and thus deprives the tumor cells of this nutrient required for protein synthesis Most normal cells can synthesize asparagine and thus are less susceptible to the action of asparaginase

Theraputic uses: L-asparginase is used to treat childhood acute lymphocytic leukemia in combination with vincristine and prednisone Adverse effects: Hypersensitivity reactions, liver affection and pancreatitis

Hydroxyurea Hydroxyurea interferes with conversion of ribonucleotides to deoxyribonucleotides by inhibiting Ribonucleotide Diphosphate Reductase. In addition, hydroxyurea blocks the incorporation of the thymidine nucleotide into the DNA strand. Melanoma; recurrent metastatic or inoperable carcinoma of the ovary

Mitotane   Adrenal carcinoma Reduces excessive steroid secretion Retenoic acid derivatives Remissions -- acute leukemia

Drug combinations

The administration of combinations of drugs in the treatment of cancer produces better results than a single drug A combination of drugs with different toxic effects and affecting different biochemical pathways has higher anti-tumour activity without additive toxicity Therapy is given intermittently to allow recovery of normal tissue i.e. bone marrow and immune system that has been affected by the drugs

Examples of drug combinations Acute lymphocytic leukemia: vincristine, methotrexate and 6-mercaptopurine Hodgkin's disease: vinblastine, doxorubicin and bleomycin Non-Hodgkin's lymphomas: cyclophosphamide, doxorubicin, vincristine

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