Canis ISSN: 2398-2942

Therapeutics: anti-neoplastic agent

Contributor(s): William Brewer Jr, Lauren Trepanier

Cytotoxic drugs

  • See also chemotherapy Chemotherapy: general principles.
  • Most act upon process of cell growth and division: potent and potentially dangerous.
    Do not use without consulting specialist oncologist.
  • Uses: for lymphoproliferative Lymphoproliferative disease and myeloproliferative Myeloproliferative tumor disorders.
  • Not very useful alone in large solid tumors.
  • Possible palliative role as adjunct to surgery or radiotherapy for metastatic conditions - combination protocols generally preferred, eg cyclophosphamide + vincristine + prednisolone for lymphoma.
  • Drug resistance can develop in tumor cells → may need to cycle drugs with different modes of action, may → multi-drug resistance.
  • Some studies suggest that multiple drug resistance in lymphoma cells in dogs can be induced by pre-treatment with glucocorticoids alone.

Toxicity

  • Not selective in action and organs with populations of rapidly growing or dividing cells, eg bone marrow and gastrointestinal mucosa are susceptible.
  • Myelosuppression (usually reversible on withdrawal of treatment) → neutropenia and risk of infection and sepsis:
    • The most common source of infection in animal cancer patients is translocation of enteric bacteria.
    • Thrombocytopenia and anemia can also occur but this is uncommon without neutropenia developing first: monitor blood counts every two weeks (up to q6 weeks if less aggressive therapy).
    • Reduce drug dosage by 20% at the next treatment with the same drug if neutrophils <1000 cells/ul.
    • Give prophylactic broad-spectrum antibacterials (potentiated sulfonamides or fluoroquinolones preferred).
    • If febrile, need IV antibiotics and intensive care.
  • Gastrointestinal toxicity → anorexia, vomiting, diarrhea:
    • 3-5 days after treatment.
    • Usually short-term, spontaneous recovery/regeneration.
    • Supportive care and fluid therapy may be required.
    • Anti-emetics.
  • Hypersensitivity reactions can occur with L-asparaginase or adriamycin.
  • Some very irritant, extravasation → local necrosis.
  • Severe vesicants will → sloughing of tissue down to bone.
  • Some have specific tissue toxicity.

Dosage

  • Low therapeutic index: dose protocols compromise between efficacy and toxicity.
  • Usually calculated as function of body surface area Body surface area because blood supply to organs of detoxification (liver and kidney) more closely related to surface area than bodyweight.
    Not to be handled by pregnant women or young children: extreme care required during handling.

Alkylating drugs

  • Most widely used chemotherapy in veterinary medicine.
  • Interfere with DNA replication by alkylating bases in DNA template.
  • Side effects: myelosuppression, inhibit gametogenesis, gastrointestinal upset, alopecia.
  • Busulphan Busulfan : selective action against granulocytes.
  • Chlorambucil Chlorambucil : slowest acting, least toxic.
  • Cyclophosphamide Cyclophosphamide : lymphoproliferative diseases; a metabolite may cause necrotising hemorrhagic cystitis.
  • Melphalan Melphalan : multiple myeloma.
  • Thiotepa Thiotepa : surface orientated (above the basement membrane) transitional cell carcinoma.
  • CCNU (Lomustine) Lomustine : lymphoma, mast cell, brain tumors.

Antimetabolites

  • Interfere with DNA and RNA synthesis by inhibiting synthesis of purines and pyrimadines.
  • Cytarabine Cytarabine : used to induce remission in lymphoproliferative or myeloproliferative diseases; CNS lymphoma; potent myelosuppressant only when given as prolonged infusion.
  • Fluorouracil Fluorouracil : carcinomas of mammary gland, gastrointestinal tract, liver and lung; at best palliative.
  • Methotrexate Methotrexate : lymphoma.
  • Mercaptopurine: immune-mediated diseases, usually given as pro-drug azathioprine Azathioprine.
  • Thioguanine: acute myelogenous leukemia.

Antitumor antibiotics

  • Interfere with synthesis of nucleic acids.
  • Bleomycin: squamous cell carcinoma.
  • Dactinomycin: lymphoma, nephroblastoma, carcinomas.
  • Doxorubicin hydrochloride Doxorubicin : anthracycline antibiotic, very effective cytotoxic drug; lympho- and myeloproliferative disorders, also palliative in soft tissue and osteogenic sarcomas and mammary, thyroid and prostate carcinomas.
    Pre-treat with antihistamines → release of histamines when administered. Can induce cardiomyopathy.
  • Epirubicin hydrochloride, less cardiotoxic alternative to doxorubicin; used as adjunct therapy in splenic hemangiosarcoma.
  • Mitoxantrone, less cardiotoxic alternative to doxorubicin.

Vinca alkaloids

  • Plant alkaloids bind to mammalian tubulin and inhibit metaphase in mitosis.
  • Cause severe extravascular reactions (less severe than doxorubicin).
  • Vinblastine sulfate Vinblastine , used along with prednisone for mast cell tumors. Causes myelosuppression.
  • Vincristine sulfate Vincristine : lymphoproliferative disorders, transmissible venereal tumor; management of thrombocytopenia; causes little myelosuppression at doses of 0.5 mg/m2 but moderate marrow suppression at 0.75 mg/m2.

Other cytotoxic drugs

  • Cisplatin Cisplatin : for osteosarcoma, soft tissue sarcoma and various carcinomas; severely nephrotoxic so has to be used in fluid (IV saline) loaded animals.
  • Dacarbazine Dacarbazine : sometimes included in combination protocols.
  • Hydroxyurea Hydroxycarbamide : used in treatment of polycythemia vera.
  • Prednisolone Prednisolone : antimitotic and cytolytic effect on lymphoid tissues; can cross the blood-brain barrier so useful in brain tumors; also for management of secondary edema.
  • Use glucocorticoids in brain tumors to reduce swelling of tissues → increased CSF pressure (effective in short-term whatever the tumor).

Immunosuppressants

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Sex hormones and hormone antagonists

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Further Reading

Publications

Refereed papers

  • Recent references from VetMed Resource and PubMed.
  • Gregory C R et al (1998) Leflunomide effectively treats naturally occurring immune-mediated and inflammatory diseases of dogs that are unresponsive to conventional therapy. Transplant Proc 30(8), 4143-4148.


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