Safety screening of drugs in cancer therapy.
Development of new drugs requires a thorough investigation of efficacy and safety of pharmaceuticals. The potential risks and benefits of drugs used in chemotherapy are carefully considered such that the benefits of using a new drug outweigh the risks in terms of the side effects caused by the drug. Damage to normal cells, tissues, organs and/or the whole organism is a big concern. Several tests are now routinely performed and are required for drug approval by various regulatory agencies around the globe. The primary goals of such preclinical safety evaluation of drugs are: (1) to identify an initial safe starting dose and subsequent dose escalation scheme to humans; (2) to identify potential target organs of toxicity and reversibility of toxicity; (3) to identify potential damage to the genetic material (genotoxicity); and (4) to identify parameters of clinical monitoring. In this paper, various models for genotoxicity assays are presented. These include: Ames assay, in vitro chromosome aberration assay and an in vivo micronucleus assay. New technologies, such as DNA adduct formation, DNA strand breakage, apoptotic changes, p53 gene expression and transgenic animal models, are also considered.
Nath
J
J
Genetics and Developmental Biology Program, West Virginia University, Morgantown 26506-6108, USA. jnath@wvu.edu
Krishna
G
G
D000782:Aneuploidy; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000592:standards; D017209:Apoptosis; D001711:Biotransformation; D002503:Centromere / Q000648:ultrastructure; D002869:Chromosome Aberrations; D004247:DNA / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation / Q000379:methods*; D016158:Genes, p53; D006801:Humans; D015162:Micronucleus Tests / Q000592:standards; D009152:Mutagenicity Tests / Q000592:standards
D000970:Antineoplastic Agents; D004247:DNA