bryostatin-1 and Stomach-Neoplasms

Bryostatin-1 is a new chemotherapeutic agent that inhibits protein kinase C. The most common side effect and the dose limiting toxicity is myalgia. The cutaneous side effects reported during the phase I and II trials were alopecia, mucositis, nonspecific "rash," "bronzing," and hyperpigmentation in sun exposed areas. No specific acute drug eruptions have been reported. We present the first reported case of a morbilliform drug eruption with histologic features of intraepidermal and subcorneal spongiotic pustules containing eosinophils secondary to bryostatin-1.

Topics: Adenocarcinoma; Antineoplastic Agents; Bryostatins; Clinical Trials as Topic; Drug Eruptions; Humans; Lactones; Macrolides; Male; Middle Aged; Protein Kinase C; Stomach Neoplasms

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 microg/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 microg/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 p34cdc2 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 p34cdc2 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-

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; CDC2 Protein Kinase; Cell Division; Energy Metabolism; Humans; Hydrogen-Ion Concentration; Lactones; Macrolides; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C3H; Mitosis; Neoplasms, Experimental; Paclitaxel; Phosphocreatine; Regional Blood Flow; Stomach Neoplasms; Tumor Cells, Cultured