Predictive value of preclinical toxicology studies for platinum anticancer drugs.

Rodent and nonrodent toxicology studies are currently expected to support Phase I trials of antineoplastic drugs in the United States. To determine the predictive value of these studies, we initiated a project to compare preclinical and clinical toxicity data within various drug classes. The first class analyzed was the platinum anticancer drugs. Twelve platinum analogues that had both preclinical (mice, rats and/or dogs) and clinical data from matching drug administration schedules were identified. The rodent LD10 (the dose that causes lethality in 10% of treated animals) or dog toxic dose high (a dose that when doubled causes lethality in dogs) correlated well with the human maximally tolerated dose on a mg/m2 basis. For every platinum analogue investigated, one-third the rodent LD10 or one-third the dog toxic dose high in mg/m2 gave a starting dose and a first escalation dose that did not exceed the clinical maximally tolerated dose. The dose-limiting toxicities in patients were previously observed in 7 of 7, 7 of 8, and 9 of 11 mouse, rat, and dog studies, respectively. Our data indicate that mice, rats, and dogs all had value in predicting a safe starting dose and the qualitative toxicities in humans for platinum anticancer compounds. The efficiency of Phase 1 trials could have been improved without sacrificing patient safety by allowing higher starting doses for this drug class than conventionally permitted.

Auditing clinical research data: objectives, applications and results.

Formal auditing of clinical research data has become a standard contemporary practice within the pharmaceutical industry. Its basic purpose is to provide documentation relevant to an assessment of the quality and integrity of data collected in the course of a clinical trial. This paper outlines the audit procedures developed within one major pharmaceutical firm. These procedures require an intensive investigation of internal and external aspects of study management, records management, data entry, data analysis and statistical report preparation. A qualitative evaluation of the results achieved by this auditing procedure are presented.

Non-specific cytotoxic cells generated in vitro in response to a weakly immunogenic murine adenocarcinoma. In vivo correlations.

Tumor 85 adenocarcinoma cells, which are very weakly immunogenic for C3H/HeN (C3H) mice, provide a model tumor system for studying the parameters of induction of a cell-mediated immune response which does not appear to be a traditional cytotoxic T-cell or NK-cell response. Mice pre-immunized with irradiated tumor 85 cells are protected about 50% of the time from a challenge of viable tumor 85 cells although it is never possible to protect 100% of the immunized mice. Optimal protection is observed in mice immunized with 10(6) irradiated tumor 85 cells 14 days prior to challenge. Protection is also observed if mice are immunized with Protection is also observed if mice are immunized with 3H or C3HfeB/HeN (C3Hf) tumors originally induced by the same carcinogen as that used to induce tumor 85. The injection of carrageenan 1 h before challenge completely reverses the protection observed in immunized mice and and tumors grow faster in carrageenan-treated immunized mice than in normal mice. Two populations of cells obtained from cultures of spleen cells stimulated by tumor 85 cells appear to prevent tumor growth in vivo. One population, which is cytotoxic for tumor 85 cells in vitro, is nylon-wool-adherent and expresses Thy 1.2. The second population, which is not observed to be cytotoxic in a 51Cr release assay, is phagocytic.