midostaurin and Ovarian-Neoplasms

N-benzoyl-staurosporine (PKC412) is a selective inhibitor of protein kinase C, and it inhibits the growth of human cancer cells. In this study, we examined the antitumor effect of PKC412, given singly and in combination with paclitaxel, on tumor regression and chemotherapeutic side effects by assessing tumor burden and cytokine production responses in vivo. Twenty-six nude mice intraperitoneally inoculated with SKOV3 cells were treated differently in 4 treatment groups: PKC412 plus paclitaxel (n = 7), paclitaxel-only (n = 6), PKC412-only (n = 6), and controls (n = 7). At autopsy, we found that PKC412 itself slightly reduced the mass of tumor but did not fully inhibit tumor formation. The incidence of evident disease was decreased when PKC412 was combined with paclitaxel (43%). From the body weight of the tumor-bearing mice, we observed that PKC412 plus paclitaxel treated mice were less wasted than paclitaxel-only treated mice (18.1 g vs 22.4 g, p = 0.001). We measured intracellular TNFalpha, IFNgamma, IL-4, and IL-10 in stimulated mouse splenocytes using flow cytometry to determine if PKC412 inhibited cytokine production in T cells. TNFalpha, IFNgamma, and IL-10 production were all significantly inhibited in the paclitaxel-treated mice. The inhibitory effects on cytokine production by paclitaxel were compensated with PKC412 combination (p = 0.008, 0.035, 0.014, respectively). From this study, we deduce that PKC412 may have clinical applications in promoting tumor regression in ovarian cancer when combined with paclitaxel. Moreover, PKC412 is able to prevent weight loss and immunosuppression induced by paclitaxel because it rescues normal proliferating cells from cytotoxic effects.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Body Weight; Cell Line, Tumor; Cytokines; Drug Therapy, Combination; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Protein Kinase C; Spleen; Staurosporine; Xenograft Model Antitumor Assays

The protein kinase C inhibitor, staurosporine derivative CGP 41 251, was more efficient than staurosporine in the reversal of decreased anthracycline uptake in the anthracycline-resistant cell subline (A2780/ADR) of ovarian carcinoma. Staurosporine was more efficient than CGP 41 251 in the induction of cytometrically determined DNA fragmentation (cytofluorometric equivalent of apoptosis) in A2780 parental human ovarian carcinoma cells compared with the drug-resistant A2780/ADR subline and in both human leukemia K-562 cells as well as mouse leukemia L1210 compared with the araC-resistant L1210 cells. Staurosporine was a more potent inhibitor than CGP 41 251 of DNA synthesis in both araC-sensitive and -resistant mouse leukemia L1210 cells. CGP 41 251 was a slightly more efficient inhibitor of thymidine incorporation than staurosporine in human leukemia K-562 cells and its combination with araC had a higher inhibitory effect on the DNA synthesis in this cell line than staurosporine. CGP 41 251 exerted DNA synthesis inhibitory effects on both araC-sensitive and -resistant L1210 cells. Staurosporine-induced DNA synthesis inhibition in both araC-resistant and -sensitive L1210 mouse leukemia cells was decreased after combined administration with araC.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Cycle; Cytarabine; DNA Replication; DNA, Neoplasm; Drug Resistance, Multiple; Drug Synergism; Female; Humans; Leukemia L1210; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mice; Mice, Inbred DBA; Neoplasm Proteins; Ovarian Neoplasms; Protein Kinase C; Staurosporine; Tumor Cells, Cultured

Topics: Alkaloids; Daunorubicin; Drug Resistance; Female; Flow Cytometry; Humans; Ovarian Neoplasms; Protein Kinase C; Staurosporine; Tumor Cells, Cultured