Rapamycin is a triene antibiotic produced by Streptonrvces hygroscopicus1,2). Structure elucidation revealed the presence of a pipecolic acid residue in the macrolide3.4). Several yeasts, as well as yeast-like and filamentous fungi, are sensitive to rapamycin; however, the main feature of the antibiotic is its high activity against Candida albicans (MIC 0.02 ~ 0.20 tcg/ml)5). Nucleic acids synthesis inhibition and degradation in C. albicans are the primary modes of action6). The LD50 ip of rapamycin in the mouse is 587 mg/kg. The antibiotic also has immuno-suppressant activity7) : it is half as potent as cyclophosphamide in inhibiting experimental allergic encephalomyelitis and is as potent as this standard reference drug in preventing adjuvant-induced arthritis. The mode of action and the pharmacological effects warranted the evaluation of rapamycin in experimental tumor models. The National Cancer Institute (NCI, Division of Cancer Treatment) conducted the initial studies and reported modest activity against P388 lymphocytic leukemia (Increased life span (ILS)=30~40% at 1.25 mg/kg) and no activity against L1210 lymphoid leukemia and Lewis lung carcinoma8). Activity was reported against B16 melanocarcinoma (ILS 80% at 100 mg/kg), Colon 26 tumor (ILS 105 % at 6.25 mg/kg) and EM ependymoblastoma (ILS 85 % at 50 mg/kg and ILS 100; at 200 mg/kg). Rapamycin was also active against the solid tumors, CD8F1 mammary tumor (80% tumor weight inhibition at 25 mg/kg) andColon 38 tumor (85% tumor weight inhibition at 25 mg/kg). Subrenal capsule CX-1 colon adenocarcinoma xenograft and spontaneous colon adenocarcinoma 11/A were sensitive to rapamycin.We report here a more detailed evaluation of the efficacy of rapamycin in transplantable tumor models. The effects of dosage, regimen and route of administration were studied. Rapamycin was compared to other antitumor agents; the antineoplastic effects of rapamycin in combination were also evaluated t Ayerst Laboratories , 567 Ridge Road, Princeton, NJ 08852, USA. >t Institut Armand-Frappier , 531, Boulevard des Prairies, Ville de Laval, Que, Canada H7V 1B7.

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Demethoxyrapamycin is a new antifungal antibiotic which is co-produced with rapamycin by Streptomyces hygroscopicus. It was isolated as a minor component during recovery of rapamycin. Its antifungal and antitumor activity is compared with that of rapamycin.

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