EX-VIVO CYTOTOXIC DRUG-EVALUATION BY DISC ASSAY TO EXPEDITE IDENTIFICATION OF CLINICAL TARGETS - RESULTS WITH 8-CHLORO-CAMP

There is a pressing need to reduce the time and cost of developing new cytotoxic agents and to accurately identify clinically active agents at an early stage. In this study, the differential staining cytotoxici ty (DISC) assay was used to assess the efficacy of the novel anti-tumo ur cAMP analogue, 8-chloro-cAMP (8-Cl-cAMP) (and its metabolite 8-Cl-a denosine) against 107 fresh specimens of human neoplastic and normal c ells. Diagnoses included chronic and acute leukaemias, myeloma, non-Ho dgkin's lymphoma (NHL) and miscellaneous solid tumours. The aim was to identify targets for subsequent phase I, II and Ill trials. 8-Cl-cAMP was tested at 4-985 mu M, along with standard chemotherapeutic drugs. 8-Cl-cAMP and its metabolite caused no morphologically observable cel l differentiation but induced dose-dependent cytotoxicity. Compared wi th untreated patients, previously treated chronic lymphocytic leukaemi a (CLL) patients showed no increase in ex vivo resistance to 8-Cl-cAMP (P = 0.878); minimal cross-resistance with other cytotoxic drugs was detected. Compared with normal cells (mean LC90 = 1803 mu M), 8-Cl-cAM P showed significant ex vivo activity against CLL (117.0 mu M; P < 0.0 001) and NHL (140.0 mu M, P < 0.0001), of which eight were mantle cell NHL (84.7 mu M), and greatest activity against cells from patients wi th acute myeloid leukaemia (AML; mean LC90 = 24.3 mu M; in vitro thera peutic index 74-fold, P < 0.0001). Solid tumour specimens were compara tively resistant to 8-Cl-cAMP. The results highlight the clinical pote ntial of 8-Cl-cAMP, point to several new phase I, II and III trial pos sibilities and provide a rationale for the inclusion of ex vivo cytoto xic drug evaluation in the drug development process.