HETEROGENOUS EFFECTS OF BRYOSTATIN ON HUMAN MYELOID-LEUKEMIA CLONOGENICITY - DOSE AND TIME SCHEDULING DEPENDENCY

The potent anti-neoplastic actions displayed in vitro by bryostatins h ave led to the introduction of short-term bryostatin-1 infusions in ph ase I clinical trials. Because bryostatin (bryo) undergoes a rapid cle arance in vivo, we were interested in its scheduling effects on acute myeloid leukemia (AML) clonogenicity. Therefore, we assessed the prima ry plating efficiency (PE(1)) of AML samples in response to several br yo concentrations after various preincubation periods in a semi-solid colony forming assay. Whereas continuous exposure to 10 nM bryo during the assay period reduced the PE(1) in nearly all samples tested, prei ncubation of eight AML patients' specimens for 1, 2, 3 or 4 days with bryo in a dose range of 0.1-10 nM showed a heterogenous PE(1) response . Stimulatory as well as inhibitory effects on leukemic clonogenic gro wth were seen within individual specimens depending on dose and preinc ubation time with no single incubation time or concentration that caus ed unequivocal common overall inhibition of clonogenic growth in most or all of the samples. Higher doses of bryo also failed to result in s pecific inhibition of leukemic cells: 4/8 samples showed an increased clonogenic response to 250 nM bryo whereas normal bone marrow progenit or cells were consistently inhibited in their clonogenicity at this do se. A marked similarity, i.e. undulatory effects with increasing bryo concentrations, was found for HL60 leukemic cells. In conclusion, the effects of bryo on clonogenic leukemia cell growth are strongly depend ent on scheduling and dose varying between and within individual AML s amples. These results caution against in vivo bryo pulse therapy, as c urrently applied, for treatment of AML. Copyright (C) 1996 Elsevier Sc ience Ltd.