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 |
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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 |
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ISSN: | 1078-0432 1557-3265 |