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細胞周期に基づく抗癌剤のがん細胞増殖抑制効果の評価モデルとUCN-01への応用：具孝庭¹、中川晋一²、臼田実男¹、山口直人²、西條 長宏^1,3、西尾和人¹（国立がんセ・研・¹薬効、²がん情報、³国立がんセ・中央病院・内科）

A cell cycle-based mathematical model for growth inhibitory effect of anticancer agents and its application for UCN-01 : Hyo-Jeong KUH¹, Shinichi NAKAGAWA², Jitsuo USUDA¹, Naohito Yamaguchi² and Nagahiro SAIJO^1,3 Kazuto NISHIO¹ (¹Pharmacol. Div., ²Cancer Inf. Epidemiol. Div., Nat'l. Cancer Ctr. Res. Inst., ³Dept. Int. Med., Nat'l Cacner Ctr. Hosp.)

Many anticancer agents induce cell cycle deregulation in tumor cells resulting in cellular growth inhibition. UCN-01 (7-hydroxyl-staurosporine), a novel anticancer agent under phase I clinical trials in US and Japan, has shown a unique cell cycle deregulation effect in vitro. For quantitative analysis of UCN-01-induced cell cycle deregulation, we developed a mathematical model of cell cycle progression. The model uses Smith & Martin theory (PNAS 70:1263,1973) and includes random transition probability (TP_i) for each cell cycle transition interface. The model assumptions are: (1) exponential growth of cell population with a first order growth rate constant (k); (2) all cells are in cycle, i.e. no G⁰ arrested cells; (3) the steady state drug effect; (4) the growth inhibition induced by UCN-01 occurs mainly via cell cycle deregulation; i.e. insignificant apoptosis. The mass balance equations for cell numbers in each cell cycle phase were written accordingly. The k was estimated from the growth curves simulated using relative transition probability (transition index, TI_i) and % of cells in each phase (P_i) obtained from FACS study. TP_i was then determined from the estimated model parameters, P_i and k. The results obtained in SBC-3 cells treated with UCN-01 for 24 hr indicated that UCN-01 suppressed the transition from G₁ to S at 0.1 μM, resulting in G₁ accumulation. At higher drug concentration, 0.8 μM, with further decrease in transition from G₁ to S, the transition from S to G₂/M was also decreased and that from G₂/M to G₁ was increased, resulting in G₁ block and G₂ abrogation. The validation and further application of the present model are in progress with respect to (1) estimation of contribution of cytostatic (cell cycle deregulation) and cytocidal effect (apoptosis) of UCN-01 and (2) analysis of cell cycle deregulation activity of other cytostatic agents.