Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro.

This study shows that combinations of bryostatin 1, a novel modulator of protein kinase C currently under clinical evaluation, with the anti-oestrogenic agent tamoxifen caused a large synergistic enhancement of growth inhibition in P388 cells in vitro. The growth-inhibitory effects of bryostatin 1 in the presence of non-inhibitory concentrations of tamoxifen were increased by approximately 200-fold, whereas growth inhibition by tamoxifen in the presence of non-inhibitory concentrations of bryostatin 1 were increased over 30-fold. These data have been confirmed by isobologram analysis. The precise mechanism underlying this effect is unknown, although preliminary data implicating protein kinase C is presented. The magnitude of this synergistic effect, together with evidence of clinical responses seen when these agents were given sequentially in ovarian cancer, merits further study.

Cross-resistance studies on two K562 sublines resistant to diaziridinylbenzoquinones.

Two resistant K562 sublines have been developed by treatment with AZQ (2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone) and BZQ (2,5-bis(2-hydroxyethylamino)-3,6-diaziridinyl-1,4-benzoquinone). The ID50 values of for AZQ on K562, the AZQ-resistant sublines (AZQR) and the BZQ-resistant sublines (BZQR) were 0.063, 1.47 and 0.244 microM, respectively. The relative ID50 values for BZQ on the same cell lines were 0.2, 0.67 and 0.83 microM, respectively. Although it is generally believed that these two quinones function by different mechanisms, the two sublines have similar decreased levels of cytochrome P-450 reductase and DT-diaphorase and increased levels of glutathione and superoxide dismutase, compared to the parent cell line. The sublines are also cross-resistant to adriamycin, mitozolamide, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and mitomycin C. This work indicates the potential multifactorial mechanisms by which drug resistance can be induced in cell lines in the absence of conventional 'P'-glycoprotein multidrug resistance.

Decreasing sensitivity to cytotoxic agents parallels increasing tumorigenicity in human fibroblasts.

Human embryo fibroblasts of common genetic origin but exhibiting a range of phenotypes from normal to aggressively tumorigenic have been used to study resistance to the cytotoxic drugs methotrexate and N-(phosphonacetyl)-L-aspartate. Measurement of the intrinsic sensitivities of these cells to the two drugs in standard survival assays, in normal fetal bovine serum, showed increasing resistance to parallel increasing tumor-igenicity. Tumor cells were totally resistant to 10 mM N-(phosphonacetyl)-L-aspartate whereas the 50% lethal dose for methotrexate for the tumor cells was 500 nM compared with 50 nM for the normal diploid parent cell line. The difference in resistance between the immortal and tumorigenic cell lines was eliminated for both methotrexate and N-(phosphonacetyl)-L-aspartate, when the experiments were repeated in the presence of dialyzed fetal bovine serum, but could be restored by the addition of either hypoxanthine (100 microM) or uridine (10 microM). This suggested an important role for the salvage pathways of purine and pyrimidine biosynthesis in the increased resistance of the more tumorigenic cell lines. The implications of these data in relation to cancer chemotherapy will be discussed.