PREDICTING HEMATOLOGICAL TOXICITY (MYELOSUPPRESSION) OF CYTOTOXIC DRUG-THERAPY FROM IN-VITRO TESTS

Several clinical oncology units are studying the roles of in vitro hem atotoxicology in phase I evaluations. At the same time, the European C enter for the Validation of Alternative Methods (ECVAM) is supporting a validation study of the C FU-GM assay [13]. It is important that the se activities be coordinated so that high-performance, optimized techn ical protocols are used for prospective and retrospective clinical eva luations. The EORTC, the NCI, and ECVAM could provide support for thes e coordinated efforts. There is an opportunity for medical oncologists involved in early clinical trials to participate in the evaluation of in vitro tests and their clinical application. Fundamental to accepta nce of these assays by oncologists and regulatory scientists, they mus t predict clinical outcome for myelosuppressive agents and then improv e phase I design and performance. These achievements would justify mor e aggressive dose escalation schemes using guidance from in vitro stud ies without compromising patient safety. Success in predicting neutrop enia might also stimulate the research required to understand how to p redict other hematologic toxicities, such as thrombocytopenia. The com plexity of a validation study in hematotoxicology is that it seeks to predict the level of exposure that causes neutropenia, in contrast to other validation studies that have sought to classify a xenobiotic as toxic or not. It may be that the clinical relevance of a new assay is not just a yes-no answer. This important distinction came from the rea lization that the xenobiotic tolerance in other organ systems of the b ody must be the same or greater than marrow in order for myelosuppress ion to be a clinical consequence of exposure. Pharmacological principl es of systemic exposure and toxicity that are integrated into the pred iction model provide the links to clinical oncology. It is also import ant to anticipate future applications of in vitro hematotoxicology. If the maximum tolerated level of drug exposure for human hematopoietic cells can be predicted, then in vitro hematotoxicology could play an i mportant role in new drug discovery. One concept involves screening fo r compounds that show efficacy at the IC level that predicts maximum t olerated exposure levels in the human [12, 22]. 'Therapeutic index-bas ed' drug discovery has been applied to the tallimustine family with so me success [21].