Application of In Vitro Chemosensitivity Testing for Evaluation of New Cytotoxic Drugs in Chronic Lymphocytic Leukaemia

Sammanfattning: Despite major advances in the understanding of the biology of chronic lymphocytic leukaemia (CLL), progress in improving its treatment has been limited and it still remains an incurable disorder. In the present research, we have performed in vitro drug sensitivity testing of primary CLL cells for preclinical evaluation of cytotoxic drugs, using the fluorometric microculture cytotoxicity assay (FMCA).The tumour type-specific activities of 14 standard drugs, evaluated in vitro on tumour cells from patients with CLL and acute leukaemias, were in good agreement with their known clinical activities. A correlation between drug treatment and development of cellular drug resistance was demonstrated in CLL, but not in the acute leukaemias. Moreover, the nucleoside analogues fludarabine, cladribine, cytarabine and gemcitabine, as well as the anthracycline idarubicin, were highly active in CLL cells.A new cytotoxic drug candidate, CHS 828, was evaluated in primary cell cultures from a broad spectrum of tumours. CHS 828 was highly active against haematological malignancies in vitro, especially CLL, but also against some solid tumours. The drug appeared to be non cross-resistant with standard drugs.In addition, the relationship between drug sensitivity in vitro and a recently described prognostic factor in CLL, the mutational status of the immunoglobulin variable heavy chain (IgVH) gene, was evaluated. Interestingly, cells with unmutated IgVH genes were more chemosensitive than the mutated cells. In summary, our results indicate that in vitro studies on tumour cellsfrom leukaemia patients may yield considerable information regarding the activity, mechanisms of action and cross-resistance of cytotoxic drugs, as well as concerning the relationship between drug sensitivity and prognostic factors, which can be useful in the preclinical evaluation of new cytotoxic drugs. Furthermore, the results suggest that the pyrimidine analogues cytarabine and gemcitabine, as well as the anthracycline idarubicin, may have a role in the treatment of CLL. The new cyanoguanidine CHS 828 is highly active in CLL cells and appears to be non cross-resistant with standard drugs. The poorer prognosis in patients with CLL cells with unmutated IgVH genes can not be explained by increased chemoresistance.