Does bioremediation reduce the biological activity of PCBs?

Cancer Chemotherapy

Dr. Jane MaddoxObjectives Understand the general adverse effects of cancer chemotherapeutic agents.

Know the mechanisms of action, specific adverse effects and mechanisms of resistance for representative drugs from each class of chemotherapeutic agents.

Introduction Cancer is the number one natural cause of death in geriatric cats and dogs, and it accounts for nearly 50 percent of deaths each year. CSU CVM&BS Animal Cancer Center.

Clemente M et al. The Veterinary Record 2009;165:78-812009 by BMJ Publishing Group LimitedInflammatory Mammary Cancer SurvivalChemotherapy:- mitoxantrone- vincristine- cyclophosphamide

Palliative treatment:- amox/clav and - glucocorticoid or NSAID(Median Survival = 57 days)(Median Survival = 35 days)Median Survival Time (weeks)5General indications and uses of chemotherapy Largely limited to small animals Principle mode of treatment for systemic cancers such as hematologic malignancies and metastatic carcinomas or sarcomas Adjuvant chemotherapy after local treatment with surgery or radiation Use of single agents or combinations of agents Cell cycle kineticsG1Synthesis of RNA and proteinSDNA synthesisSynthesis of cellular constituents for mitosisMitosisG0MG2Cell cycleGrowth fraction loosely is the fraction of cells traversing the cell cycle. Cell cycle, contd. Antineoplastic drugs are:cycle nonspecific (e.g., alkylating agents)cell cycle-specific (e.g., doxorubicin)cell cycle-phase-specific (e.g., methotrexate, vincristine)8Drug dosage and timing of chemotherapy Try to achieve maximal tumor cell killing with minimal death of normal cells Intervals are chosen to allow normal cells to recover without allowing tumor cells to replicate; or may use lower dose, more compressed metronomic therapy Dosage calculations for most cancer chemotherapeutic drugs are based on animal body surface area:Body surface area in m2 = Km x (body weight in kg)2/3 x 10-2K = 10.1 for dogs; K = 10.4 for cats9Resistance to chemotherapeutic agents Pharmacokinetic resistance: drug delivery to tumor is impaired- e.g., decreased vascularization Kinetic resistance: smaller fraction of cells in susceptible state- larger tumors generally have a smaller growth fraction Genetic resistance: development of biochemical resistance in previously susceptible cells- e.g., multidrug resistance transporter, defective drug activation, etc.

General adverse effects Bone marrow toxicity: This is the major dose-limiting toxicity in veterinary cancer chemotherapy. Myelosuppression results in: leukopenia (neutropenia) thrombocytopenia anemia

Can be treated with recombinant granulocyte-colony stimulating factor (G-CSF)

General adverse effects Gastrointestinal toxicity: Many antineoplastic drugs produce vomiting, diarrhea, anorexia and mucosal damage.Vomiting may be treated with metoclopramide or ondansetron

Alopecia: Dogs can lose hair secondary to chemotherapy (breed-dependent); cats may lose whiskers.12Cancer ChemotherapyCANCER THERAPY DRUG CLASSESAlkylating agentsAntimetabolitesMitotic inhibitorsPlatinum drugsAntitumor antibioticsMolecular targeted therapyMiscellaneous agents 131) Alkylating agents Mechanism of action: Covalent alkylation and cross-linking of DNAGenerally cycle-nonspecific Replicating cells are most susceptible Example: Cyclophosphamide, a nitrogen mustard 1) Alkylating agents, contd. Pharmacokinetics: Cyclophosphamide requires bioactivation in liver Acrolein is a toxic metabolite (bladder) Excreted by the kidneys1) Alkylating agents, contd. Specific adverse effects: Long-term treatment in dogs can result in a sterile hemorrhagic cystitis (via acrolein metabolite) Treat with hydration, diuretics, and/or sodium 2-mercaptoethane sulfonate (mesna) Clinical indications: In combination therapy for canine and feline lymphoma

162) Antimetabolites These resemble normal cellular constituents compete in enzyme reactions (to slow processes) OR replace endogenous substrates (to generate inactive products) 2) Antimetabolites, contd. Example: Methotrexate Mechanism of action: Folic acid analog- Competitive inhibition of dihydrofolate reductase - Leads to decreased synthesis of purine and pyrimidine bases- most effective in S-phase

18Folate FunctionFolic acidDihydrofolate reductase (DHFR)ThymidinePurinesTetrahydrofolateDihydrofolate MethotrexateX192) Antimetabolites, contd. Resistance: develops due to decreased uptake of the drug- Methotrexate must be actively transported into cells by a carrier-mediated process

Clinical indications: Generally limited to lymphoma2) Antimetabolites, contd. Adverse effects: GI toxicity is most common, also myelosuppression Leucovorin: a folic acid derivative that acts as an antidote to adverse effects of methotrexate 3) Mitotic inhibitors Mechanism of action: Bind to tubulin- Inhibit mitosis in M phase- Cell cycle phase-specific Examples: Vinca alkaloids - Vincristine; Taxanes - Paclitaxol3) Mitotic inhibitors, contd.Clinical indications: Lymphoma and leukemia Vincristine is the drug of choice for transmissible venereal tumors in the dogVincristine is well-tolerated by cats

3) Mitotic inhibitors, contd. Specific adverse effects: Vincristine can cause peripheral neuropathy with long-term useIrritating if extravasated

Paclitaxel: a taxane Binds to tubulin and stabilizes microtubules, preventing normal cell divisionTraditional adverse side effects included serious hypersensitivity due to carrier, but a water-soluble form now available (Paccal Vet) that eliminates the problem. Good for mast cell tumors3) Mitotic inhibitors, contd.PaclitaxelMain mechanisms of resistance - increased efflux, Multi-Drug Resistance (MDR) phenotype- altered interaction with microtubules3) Mitotic inhibitors, contd.264) Platinum drugs Examples: Cisplatin Cisplatin was developed at Serendipitous discovery

Barnett Rosenberg

274) Platinum drugs, contd. Mechanism of action: Heavy metal compounds that crosslink DNA- Inhibit DNA, RNA, and protein synthesis - Cycle nonspecific Examples: Cisplatin and Carboplatin 4) Platinum drugs, contd.Specific adverse effects: Cisplatin is contraindicated in cats due to risk of fatal pulmonary edema. Carboplatin can be given safely in cats Cisplatin is a powerful emetic Nephrotoxicity with cisplatin, but not carboplatin, is a major concern Do not use cisplatin with needles/IV sets with aluminum parts294) Platinum drugs, contd. Resistance: multiple mechanisms:- Increased expression of DNA damage/repair proteins- Decreased uptake or increased efflux of the drug- Increased inactivation of drug- Increase in antiapoptotic proteins 5) Antitumor antibiotics Example: Doxorubicin Mechanism(s) of action: - intercalates in DNA- inhibits topoisomerase II activity- generates free radicals - impairs DNA, RNA and protein synthesis - cell cycle-specific

315) Antitumor antibiotics, contd.Resistance: develops through MDR (MultiDrug Resistance) proteins

Clinical indications: Lymphoma, leukemias and a variety of carcinomas and sarcomas

5) Antitumor antibiotics, contd.Specific adverse effects Cardiotoxicity in the dog- Free radicals damage myocardium- Dexrazoxane has been used to lessen cardiac effects (iron chelator: dramatic in free radical formation) Massive local tissue damage: - if extravasation occurs6) Molecular targeted therapyTyrosine Kinase Inhibitors Toceranib (Palladia) and Masitinib (Kinavet)inhibit TK activity associated with kit, platelet-derived growth factor receptor, and (Vascular Endothelial GFR toceranib only)Direct antitumor and antiangiogenic effectsGI toxicity is main adverse effectspecifically veterinary drugs for dogs

346) Molecular targeted therapyTargeted immunotherapy Melanoma vaccine, DNA (ONCEPT)Vaccine contains human DNA sequence for tyrosinase, found only in melanocytesHuman tyrosinase seen as foreign by dog, antibodies produced against itLeads to destruction of cells containing tyrosinase (i.e., cancerous melanocytes)

357) Miscellaneous agents Corticosteroids: Prednisone and Dexamethasone: pain relief and reduction of edemadirect lymphocytotoxic effects in lymphomas and lymphoid leukemias bind to steroid receptors, altering transcription of specific genes - such as those important in cellular growth and proliferation

7) Misc. Agents: Steroids, contd. Side effects: muscle atrophy, polydipsia and polyuria

Resistance: develops due to receptors or inhibition of gene expression changes7) Miscellaneous agents cont. L-Asparaginase Some tumor cells are incapable of synthesizing asparagine and are dependent on extracellular sourcesL-asparaginase hydrolyzes asparagine, decreasing availability of this amino acid to cellsLymphoma, lymphoid leukemiasStudy guide suggestionDrug nameMechanism(s) of actionMechanism(s) of resistanceAdverse effects/toxicity