"Adriamycin - Straight Up or Liposome-Encapsulated" GULF COAST VETERINARY ONCOLOGY'S TUMOR TIDBITS Volume 2, Number 2: January 2001 This Month's Feature: Adriamycin - Straight Up or Liposome-Encapsulated DON'T FORGET TO VISIT OUR WEB SITE: CARING FOR PETS WITH CANCER, a comprehensive web site for veterinarians and pet owners caring for pets with cancer. Drug handouts, tumor handouts, case examples, pet loss information, and much more at: Editor: Kevin A. Hahn, DVM, PhD, Diplomate American College of Veterinary Internal Medicine (Specialty of Oncology) & Overall Nice Guy; Gulf Coast Veterinary Oncologists, Houston, TX 77027, drhahn@gulfcoastvetspec.com _______________________________________________________________________ Adriamycin - Straight Up or Liposome-Encapsulated Introduction Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius It is indicated in the treatment of a variety of canine and feline malignant conditions. The dose-limiting effects are myelosuppression and gastrointestinal toxicoses in both the dog and the cat, and cardiotoxicity in the dog. DOXIL® (doxorubicin HCl liposome injection) is doxorubicin hydrochloride (HCl) encapsulated in STEALTH® liposomes for intravenous administration. Greater than 90% of the drug is encapsulated in the STEALTH® liposomes. The active ingredient of DOXIL® is doxorubicin HCl. The mechanism of action of doxorubicin HCl is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations. Liposomes are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating active drugs. The STEALTH® liposomes of DOXIL® are formulated with surface-bound methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect liposomes from detection by the mononuclear phagocyte system (MPS) and to increase blood circulation time. Free doxorubicin HCl has a half-life of approximately 30 minutes in dogs and 1 hour in humans. STEALTH® liposomes have a half-life of approximately 55 hours in humans. They are stable in blood, and direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5-10% free doxorubicin) remains liposome-encapsulated during circulation. It is hypothesized that because of their small size (ca. 100 nm) and persistence in the circulation the pegylated DOXIL® liposomes are able to penetrate the altered and often compromised vasculature of tumors. They differ from conventional liposomes in their ability to avoid rapid uptake by the reticuloendothelial system, and to extravasate into tumor interstitium at a higher rate than into normal tissue. Evidence of penetration of STEALTH® liposomes from blood vessels and their entry and accumulation in tumors has been seen in mice with C-26 colon carcinoma tumors and in transgenic mice with Kaposi's sarcoma-like lesions. Once the STEALTH® liposomes distribute to the tissue compartment, the encapsulated doxorubicin HCl becomes available. The exact mechanism of release is not understood. STEALTH liposome encapsulation of doxorubicin has been shown to abrogate the myelosuppression and cumulative cardiotoxicity seen with the native compound in the canine and human systems. Dose-limiting toxicity in dogs is an ulcerative cutaneous reaction resembling palmar-plantar erythrodysesthesia (PPES), or hand-foot syndrome in humans. PPES is characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet. The syndrome is generally seen after six or more weeks of treatment but may occur earlier. The incidence of this reaction may be higher when DOXIL® is administered at doses that are higher or at intervals that are shorter than those recommended. In most patients, the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. The reaction can be severe and debilitating in some patients, however, and may require discontinuation of treatment. Experience in cats In a 1996 study, 32 cats with various malignancies were given DOXIL® as a slow IV bolus every 3 weeks. Dosages ranged from 0.75 to 1.5 mg/kg free doxorubicin equivalent as part of a phase I dose escalation trial. Doses as high as 1.5 mg/kg every 3 weeks, 50% higher than the maximum tolerated dose reported in dogs, were reported with no toxicity. Side effects observed included mild to moderate localized hyperpigmentation and alopecia, especially of the chin, mild transient gastrointestinal symptoms, and sudden explained death (2/32). The deaths occurred at lower dosages. No alterations in hemogram or biochemical profiles were noted. Responses were observed in 10 of 32 cats (31%) including 6 of 13 soft tissue sarcomas, 3 carcinomas, and one osteosarcoma. DOXIL® appears safe to administer at doses exceeding that which can be given to dogs, and exceeding the MTD for free doxorubicin in cats. Non dose-limiting cutaneous and GI side effects were well tolerated, sporadic and not dose-dependent. The causes for the two cases of acute death could not be determined. Since a MTD has not been established for cats, further studies are needed. The tumor response against feline sarcomas is of great interest and warrants further investigation. Experience in dogs In a 1996 study of 51 dogs with histologically confirmed malignancies, a total of 103 DOXIL® treatments were given IV every 3 weeks at dosages ranging from 0.75 mg/kg to 1.1 mg/kg in a phase I dose-escalation trial. The maximally tolerated dose of DOXIL® was 1.0 mg/kg IV every 3 weeks. The dose-limiting toxicity was PPES. Non dose-limiting, mild gastrointestinal toxicity was also seen, yet less frequently than with free doxorubicin treatments. No significant myelosuppression was seen. Cardiotoxicity was not noted in any dog. An overall tumor response rate of 25% was observed with 5 complete remissions and 8 partial remissions. In this study, DOXIL® appeared to be well-tolerated at dosages similar to those tolerated for free doxorubicin in tumor-bearing dogs. PPES, not myelosuppression or cardiotoxicity was the dose-limiting toxicity. DOXIL® appeared to have a broad spectrum of activity. In a follow-up study conducted in 1997, concomitant pyridoxine (vitamin B6) therapy was evaluated as a possible approach to prevent the development of PPES during DOXIL® therapy. Forty-one dogs with non-Hodgkin's lymphoma were randomized in a double-blind fashion to receive either oral pyridoxine or placebo daily during DOXIL® chemotherapy (1.0 mg/kg, i.v., every 3 weeks for a total of five treatments). Cutaneous toxicity was determined by clinical and histological scoring. No difference was observed in remission rates (71.4 versus 75%) achieved between groups. The likelihood of developing serious PPES and having to decrease or discontinue DOXIL® therapy was 4.2 times (relative risk) greater in placebo group dogs than in pyridoxine group dogs. Pyridoxine did not completely abrogate PPES; however, it occurred later and less dramatically than in placebo-treated dogs and resulted in fewer treatment delays or discontinuations, allowing a higher cumulative dose of DOXIL® to be received. Compared to the 5.0 mg/kg cumulative target dose, pyridoxine-treated dogs received a median cumulative dose of 4.7 mg/kg (mean, 4.1 mg/kg), and the placebo-treated dogs received a median of 2.75 mg/kg (mean, 2.9 mg/kg. A trend toward prolongation of remission length was observed in dogs receiving pyridoxine, which was likely attributable to their ability to receive more DOXIL® without delay or discontinuation. Summary The indications for DOXIL® appear to be similar to those of 'free' doxorubicin. Although the MTD of DOXIL® and doxorubicin are similar in the dog, the dose-limiting toxicities differ between the two drugs. In the cat, DOXIL® may be efficacious, however until an MTD can be established, the true indications and dose-limiting effects of DOXIL® in the cat remain largely unknown. _______________________________________________________________________ For further information on "Adriamycin - Straight Up or Liposome-Encapsulated" or about any other cancer issue, please call us (713-693-1166) or email Dr. Hahn at drhahn@gulfcoastvetspec.com . For more information on the web, use Medline at: