Activity of rapamycin (AY-22,989) against transplanted tumors.

Abstract

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.

Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma

“…Our "Tumor Protocol" was planned to minimize the potential impact of steroids 12 and calcineurin-inhibitors 6 on HCC recurrence, and to allow for benefits of the previously reported antitumor activity of sirolimus. [13][14][15] In the absence of a control group, we cannot conclude that our protocol prevented tumor recurrence or prolonged survival in cases with tumor recurrence.…”

Sirolimus Use and Cancer Incidence Among US Kidney Transplant Recipients

“…However, different immunosuppressant medications may have varying effects on cancer risk following transplantation. In particular, mammalian target of rapamycin (mTOR) inhibitors, a class of immunosuppressants, have anti-carcinogenic properties (3,4). The mTOR is a protein that plays a key role in an important signaling pathway that controls cellular growth and proliferation (5).…”

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

“…7 MTIs also have been shown to be active against a wide variety of tumor types. [8][9][10] We have previously shown that rapamycin induces apoptosis in precursor B ALL lines in vitro and has in vivo activity in transgenic mice with pre-B leukemia/lymphoma. 11 Second generation MTIs, CCI-779 and RAD-001, are currently in phase 1 to phase 3 clinical trials in patients with various cancers, [12][13][14][15] but preclinical studies have not previously been performed in primary human ALL.…”