Abstract
Six benzoylphenylurea (BPU) derivatives have been synthesized in Japan and extensively evaluated by the U.S. National Cancer Institute. They demonstrted potent antitumor activity in vitro against several cancer cell lines as well as in vivo against several tumor models. One of these agents, NSC639829, has now entered clinical trials. Studies have shown that these compounds are effective inhibitors of in vitro tubulin polymerization. The parent compound, NSC624548 (HO-221), has been shown to inhibit calf thymus DNA polymerase α activity. In this study we examined the effects of four BPU derivatives (NSC624548, NSC639828, NSC639829, and NSC654259) on the activity of the synthesome-associated DNA polymerase α, Escherichia coli DNA polymerase I, and calf thymus DNA polymerase α.
Among the compounds tested, only NSC624548 and NSC639828 inhibited the activities of E. coli DNA polymerase I and calf thymus DNA polymerase α. Excess DNA polymerase I or DNA polymerase α dramatically reduced the inhibition produced by these compounds. NSC624548 and NSC639828 also showed inhibitory effects of the synthesome-associated DNA polymerase α similar to that produced upon using the purified E. coli and calf thymus enzymes. All of the four compounds did not show inhibitory effect on DNA polymerase δ. The similar pattern of inhibition these compounds exert on both the purified calf thymus and the synthesome-associated DNA polymerase α offers further support for the validity of the DNA synthesome as a novel in vitro model system for studying anticancer drug action.
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Hollingshead MG, Sackett DL, Alley MC, Waud WR, Dykes DJ, Hamel E, Sausville EA: The anticancer activity of six benzoylphenylurea compounds and their interaction with tubulin. Proceedings of the 89th Annual Meeting of the American Association for Cancer Research, 39: 164, 1998
Nakajima T, Masuda H, Okamoto T, Watanabe M, Yokoyama K, Yamada N, Fujimoto S, Tsukagoshi S, Taguchi T: Antitumor activity on murine tumors of a novel antitumor benzoylphenylurea derivative, HO-221. Cancer Chemother Pharmacol 28: 351–356, 1991
Ando N, Nakajima T, Masuda H, Kawabata Y, Iwai M, Watanabe M, Kagitani Y, Yamada N, Tsukagoshi S: Antimicrotubule effects of the novel antitumor benzoylphenylurea derivative HO-221. Cancer Chemother Pharmacol 37: 63–69, 1995
Nakajima T, Okamoto T, Masuda H, Watanabe M, Yokoyama K, Yamada N, Tsukagoshi S, Taguchi T: Mechanism of tumor cell killing by HO-221, a novel antitumor compound. Cancer Chemother Pharmacol 27: 199–204, 1990
Malkas LH, Hickey RJ, Li C, Pederson N, Baril EF: A 21S enzyme complex from HeLa cells that functions in simian virus 40 DNA replication in vitro. Biochemistry 29: 6362–6374, 1990
Wu Y, Hickey R, Lawlor K, Wills P, Yu F, Ozer H, Starr R, Quan JY, Lee M, Malkas LH: A 17S multiprotein form of murine cell DNA polymerase mediates polyoma virus DNA replication in vitro. J Cell Biochem 54: 32–46, 1994
Applegren N, Hickey RJ, Kleinschmidt AM, Zhou Q, Coll J, Wills P, Swaby R, Wei Y, Quan JY, Lee MYWT, Malkas LH: Further characterization of the human cell multiprotein DNA replication complex. J Cell Biochem 59: 91–107, 1995
Coll JM, Sekowski JW, Hickey RJ, Schnaper L, Yue W, Brodie AMH, Uitto L, Syväoja JE, Malkas LH: The human breast cell DNA synthesome: its purification from tumor tissue and cell culture. Oncol Res 8: 435–447, 1996
Lin S, Hickey R, Malkas LH: The isolation of a DNA synthesome from human leukemia cells. Leuk Res 12: 501–512, 1997
Jiang HY, Hickey RJ, Abdel-Aziz W, Tom TD, Wills PW, Liu J, Malkas LH: Human cell DNA replication is mediated by a discrete multiprotein complex. J Cell Biochem 85: 762–774, 2002
Abdel-Aziz W, Jiang HY, Hickey RJ, Malkas LH: Ara-C affects formation of cancer cell DNA synthesome replication intermediates. Cancer Chemother Pharmacol 45: 312–319, 2000
Sambrook J, Fritsch EF, Maniatis T: Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, New York, 1989
Lee MY, Jiang YQ, Zhang S-J, Toomey NL: Characterization of human DNA polymerase delta and its immunochemical relationships with DNA polymerase alpha and epsilon. J Biol Chem 266: 2423–2429, 1991
Han S, Hickey RJ, Tom TD, Wills P, Syväoja JE, Malkas LH: Human cell DNA synthesome associated polymerases are inhibited differentially by the antimetabolite 1–β-D-arabinofuranosylcytosine triphosphate (ara-CTP). Biochem Pharmacol 60: 403–411, 2000
Jiang HY, Hickey RJ, Abdel-Aziz W, Malkas LH: Effects of gemcitabine and araC on in vitro DNA synthesis mediated by the human breast cell DNA synthesome. Cancer Chemother Pharmacol 45: 320–328, 2000
Coll JM, Hickey RJ, Wei Y, Malkas LH: The human cell multiprotein DNA replication complex (MRC): the effect of camptothecin on its ability to support in vitro DNA synthesis. Cancer Chemother Pharmacol 39: 97–102, 1996
Wills P, Hickey R, Ross D, Cuddy D, Malkas L: A novel in vitro model system for studying the action of ara-C. Cancer Chemother Pharmacol 38: 366–372, 1996
Wills PW, Hickey R, Malkas L: Ara-C differentially affects multiprotein forms of human cell DNA polymerase. Cancer Chemother Pharmacol 46: 193–203, 2000
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Abdel-Aziz, W., Hickey, R., Edelman, M. et al. Effect of novel benzoylphenylurea derivatives on DNA polymerase α activity using the synthesome-based in vitro model system. Invest New Drugs 21, 421–428 (2003). https://doi.org/10.1023/A:1026247101229
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DOI: https://doi.org/10.1023/A:1026247101229