van Moorsel C J, Veerman G, Bergman A M, Guechev A, Vermorken J B, Postmus P E, Peters G J
Department of Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Semin Oncol. 1997 Apr;24(2 Suppl 7):S7-17-S7-23.
Gemcitabine (2',2'-difluorodeoxycytidine) is an antineoplastic agent with clinical activity against ovarian carcinoma, small cell and non-small cell lung cancers, head and neck cancer, bladder cancer, breast cancer, and pancreatic cancer. Cisplatin (CDDP), etoposide (VP-16), and mitomycin C (MMC) are well-known anticancer agents that are also active against many of these types of cancer. Because of the low toxicity profile of gemcitabine and the differences in mechanism of cytotoxicity, combinations of these drugs with gemcitabine were studied in vitro and in vivo. Cells were exposed in vitro for 1, 4, 24, or 72 hours to gemcitabine in combination with these drugs, either simultaneously or sequentially in a constant ratio. Another approach consisted of exposure to a combination of the approximate IC25 of one drug and varying concentrations of the other drug. Synergism for several of these combinations was found in the human ovarian cancer cell line A2780, its CDDP-resistant variant ADDP, its gemcitabine-resistant variant AG6000, and in the non-small cell lung cancer cell lines H322 and Lewis lung (LL) after a 72-hour drug treatment. Studies of the possible mechanisms of action initially focused on the major metabolic features of each drug. CDDP did not enhance the accumulation of gemcitabine triphosphate and caused only marginal changes in the extent of DNA double-strand breaks (DSBs) induced by gemcitabine in these cell lines. Gemcitabine increased platinum accumulation only in the ADDP cell line, but the DNA platination was enhanced in the A2780, ADDP, AG6000, and LL cell lines. MMC did not influence the formation of DSBs by gemcitabine in the LL cell line. The combination of VP-16 and gemcitabine, however, resulted in the formation of more DSBs in this cell line than each drug alone. This effect was even more pronounced when cells were exposed to VP-16 4 hours before gemcitabine. In vivo, the antitumor activity of a combination of 50 mg/kg gemcitabine and 6 mg/kg CDDP was more effective against LL tumors than each compound alone. In conclusion, gemcitabine is an attractive drug to combine with a wide range of anticancer drugs; synergism is often schedule dependent.
吉西他滨（2'，2'-二氟脱氧胞苷）是一种抗肿瘤药物，对卵巢癌、小细胞和非小细胞肺癌、头颈癌、膀胱癌、乳腺癌及胰腺癌具有临床活性。顺铂（CDDP）、依托泊苷（VP-16）和丝裂霉素C（MMC）是众所周知的抗癌药物，对许多这类癌症也有活性。由于吉西他滨毒性较低且细胞毒性机制不同，对这些药物与吉西他滨的联合用药进行了体外和体内研究。细胞在体外以恒定比例同时或序贯暴露于吉西他滨与这些药物的组合中1、4、24或72小时。另一种方法是将细胞暴露于一种药物的近似IC25与另一种药物的不同浓度的组合中。在人卵巢癌细胞系A2780、其顺铂耐药变体ADDP、其吉西他滨耐药变体AG6000以及非小细胞肺癌细胞系H322和Lewis肺癌（LL）中，经过72小时的药物治疗后，发现其中几种组合具有协同作用。对可能的作用机制的研究最初集中在每种药物的主要代谢特征上。顺铂并未增强吉西他滨三磷酸的蓄积，且在这些细胞系中对吉西他滨诱导的DNA双链断裂（DSB）程度仅产生轻微变化。吉西他滨仅在ADDP细胞系中增加了铂的蓄积，但在A2780、ADDP、AG6000和LL细胞系中DNA铂化作用增强。丝裂霉素C在LL细胞系中不影响吉西他滨诱导的DSB形成。然而，在该细胞系中，依托泊苷与吉西他滨的联合用药比单独使用每种药物导致形成更多的DSB。当细胞在吉西他滨之前4小时暴露于依托泊苷时，这种效应更为明显。在体内，50mg/kg吉西他滨与6mg/kg顺铂的联合用药对LL肿瘤的抗肿瘤活性比单独使用每种化合物更有效。总之，吉西他滨是一种与多种抗癌药物联合使用很有吸引力的药物；协同作用通常取决于给药方案。
