Relationships of in vitro sensitivities tested with nine drugs and two types of irradiation in chronic lymphocytic leukemia

Abstract 

Extensive research into mechanisms of cytotoxic drug and irradiation resistance have produced few clinically encouraging results. In this report, we apply correlation analyses to drug and irradiation response results from a cohort of 36 classical B chronic lymphocyte leukemia (CLL) patients. Nine drugs and two types of irradiation were selected according to their usefulness in CLL therapy or on the basis of their otherwise interesting mechanisms of action. Part of the results concerning individual drugs have been previously published, but new correlation analyses are presented in this paper. Altogether 2376 duplicate cultures were performed in order to determine ID₈₀ values, i.e. doses causing an 80% inhibition in 4-day cultures when leucine incorporation was used as an indicator of cells vitality. Non-parametric Spearman’s rank order correlation confirmed a tight relationship between 2-chlorodeoxyadenosine and fludarabine, as expected. Surprisingly, correlation between two P-glycoprotein-dependent drugs, vincristine and doxorubicin, was not demonstrable. A number of entirely unexpected correlations were identified between drugs with very different mechanisms of action: (i) chlorambucil and γ-irradiation; (ii) 2-chlorodeoxyadenosine and vincristine; (iii) 2-chlorodeoxyadenosine and γ-irradiation; (iv) fludarabine and cis-platin; (v) doxorubicine and γ-irradiation; (vi) prednisolone and cyclosporin A; (vii) vincristine and verapamil. Our findings emphasize: (i) the usefulness of fresh tumor cells instead of cell lines in cytotoxicity studies; (ii) the great variation in cytotoxicity in individual patients, i.e. tumor cell heterogeneity, as well as patient heterogeneity; and (iii) an entirely unexpected finding that there were tight relationships in drug and irradiation responses between substances supposed to act with very different mechanisms.