ESTIMATION OF THE HEMATOLOGICAL TOXICITY OF MINOR-GROOVE ALKYLATORS USING TESTS ON HUMAN CORD-BLOOD CELLS

We evaluated the myelotoxicity and the anti-tumor potential of tallimu stine, three of its analogues and carzelesin, with melphalan as refere nce substance. Tallimustine was tested by clonogenic assays on both hu man bone marrow (BM) and cord blood (hCB) cells, the other compounds o n hCB only. The degree of inhibition of the haemopoietic progenitors G M-CFC, CFC-E and BFU-E was evaluated after exposure to different conce ntrations. The same schedules were tested on five tumour cell lines, W e found that the dose-response curves for tallimustine on BM and hCB c ells were similar. Carzelesin was shown to be the most potent of the s ubstances tested and to be the one with the best in vitro therapeutic index; of the distamycin analogues, the one bearing an alpha-bromoacry lic group (FCE 25450) had the best index. For melphalan, tallimustine and carzelesin, the concentration inhibiting the growth of 70% of prog enitor cells in vitro (ID70) was similar to the concentrations found i n the serum of patients treated at the maximum tolerated dose (MTD). W e conclude that hCB cells may be used instead of BM cells for in vitro myelotoxicity tests. Therapeutic indexes can be extrapolated from thi s model and could help in selecting the most promising analogue for fu rther clinical development. The in vitro-active concentrations are sim ilar to myelotoxic concentrations in patients, suggesting a predictive value for the assay.