1PHARMACOLOGY OF ANTINEOPLASTIC AGENTS(DENTAL)I.BackgroundA. Most of the recent progress using antineoplastic therapy is based on:1. Development of new combination therapies using existing drugs2. Better understanding of the mechanisms of antitumor activity3. Development of chemotherapeutic approaches to destroying micrometastases4. Understanding the molecular mechanisms concerning the initiation of tumor growth andmetastasis5 Recognition of the heterogeneity of tumorsB. Recently developed principles which have helped guide the treatment of neoplastic disease1. A single clonogenic cell can produce enough progeny to kill the host.2. Unless few malignant cells are present, host immune mechanisms do not play a significantrole in therapy of neoplastic disease.3. A given therapy results in destruction of a constant percentage as opposed to a constantnumber of cells and, therefore, cell kill follows first order kinetics.C. Malignancies which respond favorably to chemotherapy: choriocarcinoma, acute leukemia,Hodgkin's disease, Burkitt's lymphoma, Wilms' tumor, testicular carcinoma, Ewing's sarcoma,retinolbastoma in children, diffuse histiocytic lymphoma and rhabdomyosarcoma.D. Antineoplastic drugs most effective against rapidly dividing malignancies because most inhibit celldivision.2CELL CYCLEE. Indications and Contraindications1. Frequently contraindicated in case of localized neoplasm2. Effectiveness of drug in destroying malignancy3. State of health important considerationF. Drug resistance generally develops; can be due to1. Decreased cellular permeability2. Increased metabolism and excretion3. Other factorsG. Combination chemotherapy used to decrease probability of resistant populationII Antineoplastic agentsA. Alkylating agents1. Interfere with cell division in all rapidly proliferating tissues2. Most susceptible tissues are hematopoietic and GI epithelium3. Mechanism of cytotoxicity: Alkylate cellular DNA by forming carbonium ions which bindDNA guanine residue; such binding could result in:a. Miscoding of DNAb. Imidazole ring cleavagec. Excision of guanine residue producing DNA chain scissiond. Cross linkages between DNA strands; this effect thought to be primary mode ofcytotoxic action34. Development of resistance possibly due toa. Decreased cellular permeabilityb. Production of substances which compete with DNA for alkylationc. Increased rate of DNA repair5. Toxic side effectsa. Bone marrow depressionb. Nausea and vomiting especially when given I.V.c. Can get additive effects when used with ionizing radiation and antimetabolites4Commonly used alkylating agents:1. Nitrogen Mustards:a. Mechlorethamine (MUSTARGEN)i. Not orally effective; must be given I.V.ii. Side effects: emesis and bone marrow depressioniii. Primary use: generalized Hodgkin's disease and other lymphomasb. Cyclophosphamide (CYTOXAN)c. Melphalan (ALKERAN)d. Chlorambucil (LEUKERAN)e. Ifosfamide (IFEX)2. Alkyl Sulfonates: Busulfan (MYLERAN)3. Nitrosoureas:Highly lipid soluble and can cross blood brain barrier; clinicalspectrum similar to other alkylating agents but also exhibits activityagainst some solid tumors; all but streptozotocin cause significantbone marrow depressiona. Carmustine (BCNU)b. Lomustine (CCNU) and Semustine (METHYL-CCNU)c. Streptozotocin4. Ethylenimines:a. Triethylene thiophosphoramide (Thio-TEPA)b. Hexamethylmelamine (HMM, HEXASTAT)5. Triazenes:a. Dacarbazine (DTIC)5B. Natural Products1. Antimitotic DrugsVincristine and Vinblastine:a. First extracted from periwinkle plantb. Mechanism of cytotoxic action: inhibition of mitotic spindle formation by bindingtubulinc. Incomplete to moderate cross resistance between vincristine and vinblastinei. Vinblastine (VELBAN)(1) Side effects: bone marrow depression, neurotoxicity(2) Primary use: metastatic testicular tumors, Hodgkin's disease,Kaposi's sarcoma, and carcinoma of breastii Vincristine (ONCOVIN)(1) Side effects: neurotoxicity, slight bone marrow depression,thrombocytosis, hyperuricemia(2) Primary use: drug of choice for inducing remissions in childhoodleukemias (when combined with prednisone, anthracyclines andsometimes L-asparaginase); also used for advanced Hodgkin'sdisease (III and IV) when used with mechlorethamine, prednisoneand procarbazine (MOPP regimen)Paclitaxel (Taxol):a. Effective in neoplasms resistant to vinca alkaloidsb. Side effects: myelosupression and sensory neuropathy2. Epipodophyllotoxins: Etoposide (VEPESID) and Teniposide (VUMON)a. Do not bind to microtubules but fragment DNA leading to cell deathb. Primary uses: Etoposide:testicular tumors; small-cell carcinoma of the lung, non-Hodgkin's lymphomas and Kaposi's sarcoma (associated with AIDS)Teniposide: refractory acute lymphocytic leukemiac. Side effects: myelosuppression63. Antibioticsa. Dactinomycin (ACTINOMYCIN D) (COSMEGEN)i. Naturally occurring chromopeptidesMechanism of action: inhibition of RNAsynthesisAntitumor activityii. Side effects: bone marrow depression, nausea and vomiting, alopeciaiii. Primary use: rhabdomyosarcoma and Wilm's tumor in children;choriocarcinomab. Daunorubicin (CERUBIDINE), Doxorubicin (ADRIAMYCIN; RUBREX) andIdarubicin (IDAMYCIN)i. Glycosidic anthracycline antibiotics from fungusii. Mechanism of action: inhibit DNA and RNA synthesisiii. Complete cross resistance as well as with vinca alkaloidsiv. Side effects: cardiac toxicity (can be prevented by dexrazoxane); bonemarrow depressionv. Primary uses: Daunorubicin: acute lymphocytic/granulocytic leukemias; treatment ofchoice in nonlymphoblastic leukemia in adultsDoxorubicin: acute leukemia, Hodgkin's disease, non-Hodgkin'slymphomas (BACOP regimen), best available agent formetastatic thyroid CA7c. Bleomycins (BLENOXANE)i. Mechanism of action: fragment DNA chains and inhibit repairi. Given I.V. or I.M.ii. Concentrated in skin and lungsiii. Principal use: germ cell tumors of testes and ovary, e.g., testicular carcinoma (canbe curative when used with vinblastine & cisplatin)iv. Side effects: bone marrow depression (less than other antineoplastics),mucosocutaneous reactions and pulmonary fibrosisv. Other bleomycins: Plicamycin (MITHRACIN) inhibits RNA synthesis Mitomycin (MUTAMYCIN) fragments DNAd. Enzymes: L-asparaginasea. Mechanism of action: hydrolyzes asparagine, an essential amino acid to manyleukemic cellsb. Side effects: toxic to organ systems which also require asparagine, i.e., liver, kidney,CNS and clotting mechanismc. Primary use: induction of remission in acute