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.

No abstract

No abstract

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.

No abstract

Mice, inoculated intraperitoneally with TA3 ascites tumor cells, received intraperitoneal injections of D-mannose, D-glucosamine, 2-deoxy-D-glucose, and DL-glyceraldehyde. With daily single injections for 10 days, D-mannose produced no effect; D-glucosamine reduced the total tumor volume but not the packed cell volume; 2-deoxy-D-glucose caused a moderate reduction in both the tumor fluid and the packed cell volume; and DL-glyceraldehyde reduced the tumor development drastically. With multiple injections on a single day, 2-deoxy-D-glucose produced no effect; D-glucosamine caused a moderate inhibition of tumor growth; and DL-glyceraldehyde strongly inhibited the tumor development. The inhibitory effect of DL-glyceraldehyde was greatly enhanced by the previous immunization of the mice with an insoluble fraction prepared from the tumor cells. The potentiating effect of DL-glyceraldehyde and immunization was found also with the Ehrlich, Ehrlich-Lettré, 6C3HED, and SAI mouse ascites tumors. DL-Glyceraldehyde was toxic to mice with an LD50 of 3.0 g/kg. Mice, injected intraperitoneally with 1.0% DL-glyceraldehyde solution, developed enlarged livers which showed excessive amounts of cytoplasmic glycoprotein granules.

Aminophenyl mercuric acetate (APMA)-activated collagenase (C) (60 U/ml) obtained from in vitro cultures of human skin fibroblasts or recombinant interleukin-1 beta (IL-1 beta) (200 U/ml) was infused continuously for 7 days into the rabbit knee synovial space by means of an implanted Alzet osmotic pump. In stability studies in vitro, activated C or IL-1 incubated for 7 days at 37 degrees C, showed no significant loss of biological activity. Alterations in knee cartilage morphology and proteoglycan (PG) content were determined histologically, and the incidence of cartilage damage calculated. C or IL-1 vehicles infused for 7 days, caused no damage. Incidences of damage for C or IL-1 (n = 8-9), respectively, were as follows: loss PG: 88% and 100%; chondrocyte disorganization and loss, 50% and 78%, fissures and or fraying, 25% and 78%; and convergence of inflammatory cells, 25% and 66%. These results confirm the important role of C and IL-1 in cartilage damage.

No abstract