Wilkoff L J, Dulmadge D A, Laster W R, Griswold D P
Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, AL 35255-5305.
Cancer Chemother Pharmacol. 1989;23(3):145-50. doi: 10.1007/BF00267945.
Cultured murine leukemia P388 cell populations were derived from P388 cells resistant to vincristine (P388/VCR), adriamycin (P388/ADR), and 1-beta-D-arabinofuranosylcytosine (P388/ARA-C) that were developed in vivo and to the parental drug-sensitive cells (P388/O) that were passaged in vivo. The doubling times of the cultured cell populations (mean +/- SD) between cell densities of 5 x 10(4) and 1 x 10(6) cells/ml were 14.2 +/- 2 h (P388/O), 16.5 +/- 1.9 h (P388/VCR), 16.9 +/- 1.2 h (P388/ADR), and 15.0 +/- 1.4 h (P388/ARA-C). Exponentially proliferating cultured cell populations were exposed to selected homoharringtonine (HHT) concentrations for 24 h and the surviving cell fractions were determined by colony formation in semisolid medium. The results, based on differential sensitivity of the cell populations to HHT, indicated that cultured P388/VCR cells were cross-resistant to 0.018-1.8 micrograms/ml HHT, P388/ADR cells were cross-resistant to 0.058-1.8 micrograms/ml HHT, and P388/ARA-C cells were collaterally sensitive to 0.09-0.36 micrograms/ml HHT. The results with the cultured P388/VCR, P388/ADR, P388/ARA-C, and P388/O cell populations were confirmed in animal experiments. CD2F1 mice bearing intraperitoneal (i.p.) implants of 1 x 10(6) P388/VCR, P388/ADR, P388/ARA-C, or P388/O leukemia cells were given HHT i.p. qd on days 1-9 postimplantation. Optimal treatment (less than or equal to LD10) produced in vivo cell kills of 2 to 3 log10 units in P388/O and about 7 log10 units in P388/ARA-C, whereas P388/VCR and P388/ADR cells actually increased by 1-2 log10 units during treatment. The results of this study indicate that cross-resistance (P388/VCR and P388/ADR) or collateral sensitivity to HHT (P388/ARA-C) is a function of the cellular properties of the target tumor cell populations that is independent of host factors.
培养的小鼠白血病P388细胞群体源自对长春新碱（P388/VCR）、阿霉素（P388/ADR）和1-β-D-阿拉伯呋喃糖基胞嘧啶（P388/ARA-C）具有抗性的P388细胞，这些抗性细胞是在体内培育出来的，同时还包括在体内传代的亲代药物敏感细胞（P388/O）。在细胞密度为5×10⁴至1×10⁶个细胞/毫升之间时，培养的细胞群体（平均值±标准差）的倍增时间分别为：14.2±2小时（P388/O）、16.5±1.9小时（P388/VCR）、16.9±1.2小时（P388/ADR）和15.0±1.4小时（P388/ARA-C）。将指数增殖的培养细胞群体暴露于选定浓度的高三尖杉酯碱（HHT）中24小时，通过在半固体培养基中形成集落来测定存活细胞分数。基于细胞群体对HHT的不同敏感性的结果表明，培养的P388/VCR细胞对0.018至1.8微克/毫升的HHT具有交叉抗性，P388/ADR细胞对0.058至1.8微克/毫升的HHT具有交叉抗性，而P388/ARA-C细胞对0.09至0.36微克/毫升的HHT具有侧链敏感性。对培养的P388/VCR、P388/ADR、P388/ARA-C和P388/O细胞群体的研究结果在动物实验中得到了证实。将植入1×10⁶个P388/VCR、P388/ADR、P388/ARA-C或P388/O白血病细胞的CD2F1小鼠在植入后第1至9天每天腹腔注射HHT。最佳治疗（≤LD10）在体内使P388/O细胞杀伤2至3个对数10单位，使P388/ARA-C细胞杀伤约7个对数10单位，而P388/VCR和P388/ADR细胞在治疗期间实际上增加了1至2个对数10单位。本研究结果表明，对HHT的交叉抗性（P388/VCR和P388/ADR）或侧链敏感性（P388/ARA-C）是靶肿瘤细胞群体细胞特性的一种功能，与宿主因素无关。
