A ROLE FOR PACLITAXEL IN THE COMBINATION CHEMOTHERAPY OF ACUTE MYELOBLASTIC-LEUKEMIA - PRECLINICAL CELL-CULTURE STUDIES

Paclitaxel dose responses in culture have been investigated alone and in association with cytosine arabinoside (ARA-C) and all-trans retinoi c acid (ATRA), with the objective of identifying a role for paclitaxel in the treatment of acute myeloblastic leukaemia (AML). Initial studi es were done lo determine if paclitaxel dose responses of AML blast ce ll precursors were altered by regulatory compounds known to modify the dose responses of ARA-C. In contrast to ARA-C, paclitaxel dose respon ses were independent of cell culture method, the growth factors G-CSF and GM-CSFI and the ligands all-trans retinoic acid (ATRA) and hydroco rtisone. Most blast cell populations were sensitive to paclitaxel; com pared with normal marrow progenitors the Close responses were markedly hel-erogenous with some more, and others less, sensitive. Remission m arrow progenitor paclitaxel responses resembled those of AML blasts in heterogeneity. The cell culture model tested the effect of paclitaxel and ATRA on the ARA-C dose responses of OCI/AML-5: paclitaxel exposur e was either before or after ARA-C to test for an effect of schedule; ATRA was added to the MEC cultures after p!aclitaxel and ARA-C. Repeat experiments were done to test three dose levels each of paclitaxel an d ATRA. When paclitaxel was given after ARA-C, synergism was found for all but one of the dose combinations tested; only three examples of s ynergy were seen when paclitaxel preceded ARA-C. The studies justify t rials combining ARA-C, paclitaxel and ATRA using a schedule suggested by the cell culture findings.