Barbara E. Kitchell, DVM, PhD, DACVIM
There are six general classes of chemotherapy drugs, based on their mechanisms of action.
Alkylating agents in the classical family include nitrogen mustard, cyclophosphamide, chlorambucil, melphalan, busulfan, and Ifosfamide. They act by cross-linking strands of DNA, particularly at the N-7 position of guanine. They are cell cycle phase nonspecific, and are thus active during most parts of the cell cycle. Side effects seen include: myelosuppression, gastrointestinal toxicity, and sterile hemorrhagic cystitis (cyclophosphamide and iphosphamide. Ifosfamide must be given with the bladder-sparing agent Mesna, to avoid severe urothelial injury).
Other drugs classed as alkylating agents include: the nitrosoureas (CCNU and BCNU); the tetrazines (DTIC, or dacarbazine); the aziridines (thiotepa and mitomycin C); and the non-classical alkylating agents such as procarbazine and hexamethylmelamine. These agents also form covalent cross-links in DNA, more typically at the 0-6 position of guanine as the most important DNA adduct site, and have the primary adverse effects of myelosuppression and GI toxicity.
Antimetabolites act during the S phase of the cell cycle, usually by mimicking normal purines and pyrimidines, which are the building blocks of DNA. Drugs in the category include: methotrexate and 5-fluorouracil (folic acid antagonists); azathioprine, mercaptopurine, and 6-thioguanine (purine antagonists); and cytosine arabinoside and gemcitabine (pyrimidine antagonists). Another useful antimetabolite is L-asparaginase, an enzyme that inhibits lymphoma cells with an absolute requirement for the pre-formed amino acid asparagine. L-asparaginase starves cancer cells without affecting normal cells, which are capable of making asparagine from other amino acids, whereas the lymphoma cells generally cannot. The newest agent in this class to be used in veterinary medicine is the fluorinated cytidine analog gemcitabine. Toxicities seen include: myelosuppression and gastrointestinal toxicity (especially methotrexate).
Antitumor antibiotics or topoisomerase inhibitors include doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, and bleomycin. These are particularly potent drugs, with doxorubicin used most commonly in veterinary medicine. Mechanisms of action include intercalation of DNA and interference with topoisomerase enzyme function. The presence of antitumor antibiotics within the structure of DNA induced failure to replicate DNA, impaired protein production through interference with transcription of messenger RNA, and chromosomal strand breaks caused by interference with the unwinding of DNA via topoisomerase. Toxicities include: myelosuppression, GI signs, cardiac (doxorubicin), pulmonary (bleomycin) and renal (doxorubicin in cats), perivascular sloughing, anaphylaxis, and alopecia.
Plant alkaloids are mitotic spindle poisons active in G2 and M phases of cell division (vinca alkaloids, taxanes) or are topoisomerase interactive agents (etoposide and teniposide). They are derived from periwinkle (Vinca rosea) and mayapple (Podophyllum peltatum) plants. Vincristine and vinblastine are most commonly used, and new drugs such as etoposide, teniposide, and vinorelbine are being used in human medicine but have not yet received widespread use in veterinary oncology. The use of the newer agents in the taxane class (paclitaxel and docetaxel) is being explored in veterinary medicine as these agents are highly effective in human medicine. These compounds are derived from the bark or needles of the Pacific yew tree (Taxus brevifolia). However, the taxanes are extremely anaphylactogenic due to the use of Cremaphor-EL to solubilize the formulation of the drugs, which are not water-soluble compounds. The taxanes must be administered with extensive and thorough premedication with steroids and antihistamines. Toxicities associated with vincristine are mild, but perivascular reaction can be a problem. Vinblastine is more myelosuppressive than is vincristine in general. Myelosuppression accompanies the use of other drugs in this class, and anaphylaxis is the greatest problem associated with administration of taxanes, along with myelosuppression and GI toxicity.
Hormones are used in the palliation of certain human and animal tumors. The most used hormones in veterinary medicine are corticosteroids, which are helpful in mast cell tumors, lymphomas, and lymphoid leukemias. The mechanism of action by which steroids kill cancer cells is thought to be through altered cellular transport of nutrients, induction of apoptosis (programmed cell death), and induction of cellular differentiation.
Platinum agents have gained wide use in veterinary medicine. Cisplatin and carboplatin both appear to be effective and tolerable agents. They act by cross-linking DNA, generally at the guanine base. Toxicities: Cisplatin is highly nephrotoxic and must be given with extensive fluid diuresis. Carboplatin is not nephrotoxic but is renally cleared so care must be taken when giving carbo to patients with mild renal insufficiency. Cisplatin is not for use in cats, as it causes a fatal pulmonary edema in this species.
Examples of dose modifications for veterinary clinical medicine
Because of the concern regarding inaccuracies of the meter-square basis of drug dosing in veterinary medicine, the following modifications in drug dose may be extremely helpful if toxicity is to be avoided in veterinary cancer patients. Current dose structures (again, empirically derived) are as follows (based on lean body weight and general good health):
Cyclophosphamide. 50 mg/M2 BSA PO alternate day, not to exceed 8 weeks duration therapy in dogs. Cats should receive a 25 mg tablet twice weekly for 6 weeks. Alternate means of administration are by IV bolus injection of 150-300 mg/M2 cyclophosphamide every 3 weeks or according to protocol rotation schedule, which should be administered with furosemide concurrently to minimize risk of sterile hemorrhage cystitis. Low dose intermittent oral therapy minimizes myelosuppression, GI toxicity and sterile hemorrhagic cystitis.
Doxorubicin. Doxorubicin (adriamycin) can be administered as a 1 mg/kg dose or the following sliding scale can be used: Dogs < 10 pounds 20 mg/M2; 10-20 pounds 25 mg/M2; 70-85 pounds 35 mg/M2; 85-110 pounds 40 mg/M2; > 110 pounds 45 mg/M2. These doses are given at 21-day intervals, and are based on lean body weight and on prescreening ECGs for normal cardiac function! Be careful of breed sensitivities: Shelties, Collies, Westies, Yorkies (GI toxicity); Dobes, Rotts, Boxers (subclinical cardiomyopathy--always echo these). Cats receive 1 mg/kg body weight every 3 to 4 weeks (interval based on degree of anorexia and lethargy the week after therapy).
Actinomycin D. Dosed on a sliding scale: Dogs <20 pounds 0.5 mg/M2; 20-60 pounds 0.7 mg/M2; > 60 pounds 1.0 mg/M2. We perform dose escalation with this drug. If a dog can tolerate a given dose level, we try to increase by 0.1 mg/M2 with each successive dose until toxicity is reached. Can be given at 2-3 week intervals. We have limited experience with this drug in cats.
Cisplatin. Dosed on a sliding scale: Dogs < 20 pounds 50 mg/M2 (note, <10 pounds may become toxic on this dose and may require lower doses); 20-60 pounds 60 mg/M2; >60 pounds 70 mg/M2 every 3 or 4 weeks depending upon adverse GI effects; must have normal renal function. Renal protection is provided by an extensive fluid diuresis regimen, typically involving 18.6 ml/kg/hr of 0.9% saline for 4 hours, followed by a 20-minute cisplatin infusion at the same fluid rate, and a 2 hour period of post-diuresis at this rate. Because cisplatin is a potent emetogen, antiemetic premedication is required. An IM injection of 0.2 mg/kg of butorphanol may be successfully used for this purpose 30 minutes before cisplatin administration, and injectable metaclopromide at standard doses may be added at the end of the infusion as needed. Not for use in cats.
Carboplatin. We generally administer 300 mg/m2 BSA to dogs, but will perform a dose reduction for smaller dogs or dogs with moderate renal insufficiency. Dogs <10 pounds 200 mg/M2; 10-20 pounds 250 mg/M2; > 20 pounds 300 mg/M2. In the case of renal insufficiency, we do not administer carboplatin to dogs with a serum creatinine level greater than 3 mg/dl. We give 200 mg/M2 to dogs with serum creatinine levels of 2.5 mg/dl, and 250 mg/M2 to dogs with creatinine levels of 2.0 mg/dl. Cats receive 180-240 mg/M2, depending upon the size and health status of the particular patient.
DTIC (Dacarbazine). Two administration protocols are available. Dacarbazine can be used as 800 mg/M2 IV infusion over 8 hours every 3-4 weeks. We recommend that dogs receiving the 8 hour infusion be hospitalized overnight so that management of nausea and vomiting can be accomplished. We often add a constant rate infusion metaclopromide drip overnight after the 8 hour infusion of DTIC. Alternately, DTIC may be dosed as 200 mg/M2 IV slow push daily for 5 consecutive days. CBC before the 4th dose may allow for postponement of doses 4 and 5 to avoid significant GI and marrow toxicity. Not for use in cats.
Vincristine. Generally dosed 0.5 mg/M2 IV weekly. Dose escalation may be applied to this drug, with large dogs tolerating up to 0.75 mg/M2 (GI toxicity becomes the limiting factor, with some myelosuppression noted at high dose).
Vinblastine. This drug is a structural analog of vincristine. The dose is 2.0 mg/M2 IV, with the dosing interval dependent upon the combination protocol prescribed. It is important to note that vincristine and vinblastine are not the same agent. The most common accidentally overdosed chemotherapeutic agent in human and veterinary medicine is vincristine, which is mistakenly administered at the vinblastine dose.
Chlorambucil. This drug has traditionally been underdosed in the veterinary literature (hence has been associated with minimal toxicity). We currently administer 4 mg/M2 PO alternate day for dogs as lymphoma and mast cell tumor maintenance. Because pills should not be split, cats should be given a 2 mg tablet twice weekly. Published protocols that call for high dose intermittent bolus administration of chlorambucil (i.e., 20 mg/m2 PO q 21 days) may be associated with neurologic toxicity, including myoclonus and seizure activity.
L-Asparaginase. This drug is an enzyme which depletes the plasma of the amino acid asparagine. The use of this drug is largely limited to lymphoblastic lymphoma or leukemia, because these cells require pre-formed asparagine to make proteins. Other normal cells of the body have sufficient asparagine synthase activity to replace the amino acid. Dose in dogs is 10,000 international units SQ or IM, and in cats 400 units/kg. The drug is administered in short courses to prevent the onset of drug resistance through up regulation of asparagine synthase asparagine synthase expression.