"Principles of Chemotherapy" TUMOR TIDBITS, A BIWEEKLY EMAIL NEWSLETTER FROM GULF COAST VETERINARY ONCOLOGY Number 71; September 27, 2002. ======================================================================= THIS WEEK'S TUMOR TIDBIT: PRINCIPLES OF CHEMOTHERAPY ======================================================================= As a follow-up to last week's Tidbit on "when should chemotherapy be considered", this week's Tidbit briefly (hence the name Tidbit) reviews some issues of chemotherapy drug pharmacology. This is important to review prior to drug and protocol selection for the patient. This means that next week's Tidbit will focus on drug protocol selection. PHARMACOLOGIC PRINCIPLES OF CHEMOTHERAPY In order to induce remission without harming the patient, anticancer drugs must damage tumor cells to a greater degree than normal cells. Cytotoxicity refers to the chemotherapeutic action of a drug. The mechanism of cytotoxicity varies with each drug class. In general, however, efficacy is greatest against actively cycling cells, and some agents act specifically on cells in certain phases of the cell cycle. Knowledge of the mechanism of action for each drug will allow the use of drug combinations that may act synergistically, and avoid drugs that may antagonize each other's mechanism of action. When a cytotoxic drug is administered to a population of cells, the number of cells killed will not be absolute, but will be a percentage of the total number. If a tumor containing one billion cells is exposed to a dose of drug that kills 99% of the population, 990,000,000 cells will be killed and 1,000,000 (one million) will remain, but the tumor will now be clinically undetectable. If the tumor starts at a mass of 100 g, or one trillion cells, then after chemotherapy 1 billion will survive; the drug has been equally effective but the tumor will remain clinically detectable. The cytotoxic action of chemotherapeutic agents is dependent on concentration over time rather than peak plasma levels, whereas peak plasma level often determines adverse effects on normal tissue. This makes the use of slow infusion techniques desirable for intravenous drugs. DOSE RESPONSE CURVE For all effective drugs, a sigmoid curve can be defined between the dose administered and the effect, such as percentage of cells killed. This curve exists for normal cells as well as for tumor cells. An ideal drug has a response curve with a steep slope for tumor cells and a gradual slope for normal cells; furthermore, the therapeutic dose should fall on the linear portion of the curve for tumor cells and at the foot of the curve for normal cells. Thus a small increase in dose brings about a large increase in tumor response and a small increase in toxicity. The curve plateaus at a point of maximal effect, beyond which any further increase in dose will not increase the response. THERAPEUTIC INDEX As with other medications, the therapeutic index refers to the ratio of the toxic dose to the effective antitumor dose. The therapeutic index of most chemotherapeutic agents is relatively low, necessitating careful dosing. Improvements in therapeutic index can be made by using techniques that either make the drug more effective or protect against toxic effects. The optimum dose is at the point on the dose response curve where maximum antitumor effect and acceptable toxicity occur. It may be necessary to accept some toxicity or some risk of incomplete response, or both. In practice, the optimum dose in a given circumstance depends on the goal of therapy. If the goal is cure, toxic risks are likely. If palliation is the goal, toxicity will be avoided, but incomplete response is likely. Toxicity from chemotherapeutic agents ranges from mild to life threatening. Tissues with high growth fractions such as bone marrow and epithelial tissues, including the gastrointestinal tract, are normally most susceptible to toxic side effects. Some drugs have additional toxic effects on other tissues, such as urinary tract, myocardium, or pancreas. These effects may be unrelated to the cytotoxic effects and may be idiosyncratic or species specific. Anaphylaxis is of concern in the use of certain drugs, as a reaction to either the drug itself or the carrier. DRUG CLASSES The major classes of chemotherapy agents are the alkylating agents, antimetabolites, mitotic inhibitors such as plant alkaloids and podophyllotoxins, and antibiotics. Two additional important agents are the platinum compounds and the enzyme L-asparaginase. The alkylating agents are the largest and oldest group and are not cell cycle specific. The antibiotics have a variety of mechanisms of action, and the most commonly used are the anthracyclines (doxorubicin or Adriamycin). The toxic side effects of some chemotherapy agents can be specifically antagonized or minimized by the use of special administration techniques, such as saline diuresis before administration of cisplatin to minimize renal toxicity, or a second drug, which does not have direct antitumor effect, but does allow the use of higher doses because of an increased therapeutic index. An example is the use of Mesna to prevent hemorrhagic cystitis caused by ifosfamide. ======================================================================= SUGGESTED READING Veterinary Oncology, From "The Practical Veterinarian Series". By Hahn KA. Butterworth-Heinemann Press, 2002. ======================================================================= We hope this info helps and don't hesitate to call us Gulf Coast Veterinary Oncology! Kevin A. Hahn, DVM, Phd, Diplomate ACVIM (Oncology), drhahn@gcvs.com Janet K. Carreras, VMD, Residency Completed and Certification Examination Passed, ACVIM (Oncology), drcarreras@gcvs.com Glen K. King, DVM, MS, Diplomate ACVR (Radiology & Radiation Therapy), drking@gcvs.com Gulf Coast Veterinary Diagnostic Imaging & Oncology 1111 West Loop South, Suite 150, Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 W: www.gcvs.com