The in Vivo Effect of Bryostatin-1 on Paclitaxel-induced Tumor Growth, Mitotic Entry, and Blood Flow

Pretreatment of tumor cells with the protein kinase C (PKC) inhibitor bryostatin-1 enhances the cytotoxicity of most chemotherapeutic agents. However, in the case of paclitaxel, this effect has been shown in vitro to be best achieved when bryostatin-1 follows (rather than precedes) paclitaxel treatm...

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Veröffentlicht in:Clinical cancer research 2000-04, Vol.6 (4), p.1498-1507
Hauptverfasser: Koutcher, J A, Motwani, M, Zakian, K L, Li, X K, Matei, C, Dyke, J P, Ballon, D, Yoo, H H, Schwartz, G K
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Sprache:eng
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Zusammenfassung:Pretreatment of tumor cells with the protein kinase C (PKC) inhibitor bryostatin-1 enhances the cytotoxicity of most chemotherapeutic agents. However, in the case of paclitaxel, this effect has been shown in vitro to be best achieved when bryostatin-1 follows (rather than precedes) paclitaxel treatment. With combination trials of bryostatin-1 and paclitaxel planned for clinical trials and with only in vitro data available regarding drug sequence, we elected to undertake an in vivo study evaluating the effect of sequential bryostatin-1 and paclitaxel in a tumor-bearing mouse model and to correlate this effect to cell cycle events, tumor metabolism, and tumor blood flow. At the maximum tolerated i.p. dose, bryostatin-1 at 80 μg/kg resulted in a small but significant increase in tumor doubling time (4.2 ± 0.3 days) compared with control tumors (3.0 ± 0.3 days; P < 0.01). Mice treated with i.v. paclitaxel, administered at a dose of 12 mg/kg every 12 h for three doses, weekly for 3 weeks, had a tumor doubling time of 23.4 ± 1.7 days. Mice pretreated with i.p. bryostatin-1 (80 μg/kg) followed 12 h later by i.v. paclitaxel (12 mg/kg every 12h for three doses) weekly for 3 weeks had a tumor doubling time of 9.7 ± 1.1 days. This was significantly less ( P < .001) than paclitaxel alone, which indicated an inhibitory effect by bryostatin-1 on paclitaxel therapy. In comparison, tumor-bearing mice that were treated with the same dose but with the sequence of paclitaxel followed by bryostatin-1 had a tumor doubling time of 29.6 ± 0.6 days. This was significantly greater than the tumor doubling times for any condition tested ( P < 0.01), demonstrating the sequence dependence of this combination. The efficacy of paclitaxel is dependent on mitotic entry, a step that requires activation of p34 cdc2 kinase activity. Treatment with paclitaxel in vivo increased p34 cdc2 kinase activity in the mouse mammary tumors, whereas administration of bryostatin-1 before paclitaxel prevented the p34 cdc2 kinase activation by paclitaxel. This was further evaluated in vitro by flow cytometry in MKN-74 human gastric cancer cells. As determined by MPM-2 labeling, which identifies cells in mitosis, pretreatment with bryostatin-1 prevented paclitaxel-treated cells from entering mitosis. Bryostatin-1 has been reported to induce changes in muscle metabolism and to decrease muscle blood flow. These events could impact on the interaction of bryostatin-1 with paclitaxel. Using proton-decoupled phosp
ISSN:1078-0432
1557-3265