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Annals of Clinical & Laboratory Science 36:455-460 (2006)
© 2006 Association of Clinical Scientists

Antitumor and Normal Cell Protective Effect of PKC412 in the Athymic Mouse Model of Ovarian Cancer

Myungshin Kim1, In-Yang Park2, Jihyang Lim1, Yonggoo Kim1, Ku Taek Han2, Won Heui Chung1 and Kyungja Han1
1 Department of Laboratory Medicine and 2 Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea

Address correspondence to Kyungja Han, M.D., Department of Laboratory Medicine, St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 62 Youido-dong, Youngdeungpo-gu, Seoul 150-713, Korea; tel 82 2 3779 1310; fax 82 2 3779 2285; e-mail microkim{at}catholic.ac.kr.

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 TNF{alpha}, IFN{gamma}, IL-4, and IL-10 in stimulated mouse splenocytes using flow cytometry to determine if PKC412 inhibited cytokine production in T cells. TNF{alpha}, IFN{gamma}, 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.

Keywords: protein kinase C inhibitor, ovarian cancer, paclitaxel, PKC412, cytokine






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