Prediction of drug toxicity in. man Antidepressant activity of cyclazocine Dosage forms of chlorpromazine Effect of stress on central actions of scopolamine Atropine and pralidoxime combination Diuretic action of an azido pyrimidinePerhexiline maleate
The usefulness of dogs and monkeys in predicting potential qualitative drug toxicity in man was examined retrospectively for twenty‐five anticancer compounds of diverse chemical and functional classification. It was found that the large animal screen served to alert the physician to a significant proportion of the total spectrum of drug effects, which were encountered during the clinical use of a new toxic compound. The dog and monkey correctly predicted bone marrow depression, gastrointestinal disturbance, and hepatotoxicity for each drug producing these effects in the clinic; in the case of renal, cardiovascular, and neuromuscular toxicity, however, the large animal screen failed in each instance to predict one drug that produced these toxicities in man. The correct predictions were accomplished at the expense of a high percentage of false positives, which resulted from the necessity of using severely toxic dose levels in order to demonstrate all potential toxicities inherent in any compound. While organ system toxicity observed during an animal study can never be disregarded, it should be viewed with an understanding of certain limitations of animal toxicologic data. While toxicity may develop in man in an organ system predicted susceptible by an animal, a different specific clinical or chemical parameter may be involved. The adverse reaction may appear in man at a greater or lesser dose level or may follow a different order of appearance in relationship to the total spectrum of qualitative toxicity inherent in the compound.
545 Background: CALGB 9342 was designed to test the efficacy of paclitaxel in women with advanced breast cancer. Tissue blocks were collected to retrospectively assess single gene markers (Lin et al, ASCO 2004, Abstract # 9562). RNA profiling has been able to classify tumors into biologic subtypes: ER/PR positive, HER2 amplified and basal-like (ER/PR/HER2 negative) (Perou et al, Nature 2001). To assess the feasibility of performing RNA microarray from this archived material, a pilot study was performed to determine if tumor subtypes could be identified by gene expression profiles. Methods: Primary tumors diagnosed between 1990–97 from women with metastatic breast cancer enrolled on CALGB 9342 were selected. Thirty formalin fixed, paraffin-embedded (FFPE) tissue blocks were selected based on HER2 by FISH (Vysis Pathvysion.), estrogen and progesterone receptor status (from pathology report) to equally represent three categories of breast cancer: HER2 amplified, ER and/or PR positive, ER/PR/HER2 negative. 4 uM tissue sections were macrodissected, RNA was isolated, linearly amplified, hybridized to two microarray platforms (Custom Agilent 22K gene chip, Affymetrix X3P whole genome array) using appropriate labeling methods. Tumors were classified by gene expression pattern using intrinsic signature genes and the ability to predict biomarker status was subsequently determined. Results: Twenty-eight of 30 cases could be successfully amplified and hybridized for microarray profiling. Ten percent of Agilent arrays and 20% of Affymetrix arrays were of poor quality. Both Agilent Whole Genome Chip and the Affymetrix X3P array correctly classified 9/10 HER2 positive, 8/9 ER/PR positive and 9/9 triple negative cases. Neither poor quality nor misclassification could be explained by year of embedding of the primary tumor. Conclusions: Microarray profiling from archived, FFPE tissue from cooperative group clinical trials is able to correctly classify tumor subtypes in the majority of cases. This data suggests that microarray profiling from large cohorts of archived tissue may be feasible to search for gene expression patterns that predict outcome. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Arcturus Arcturus
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