Lee S M, Thatcher N, Dougal M, Margison G P
CRC Dept of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK.
Br J Cancer. 1993 Feb;67(2):216-21. doi: 10.1038/bjc.1993.42.
There is increasing experimental evidence to suggest that endogenous expression of O6-alkylguanine-DNA-alkyltransferase (ATase) is a major factor in cellular resistance to certain chemotherapeutic agents including dacarbazine (DTIC). We have recently shown wide interindividual variation in the depletion and subsequent regeneration of ATase in peripheral blood mononuclear cells (PMCs) following DTIC and this has now been extended to ascertain whether or not depletion is related to dosage of DTIC used and repeated treatment cycles of chemotherapy. ATase levels were measured in three groups of 25 patients (pts) up to 24 h after receiving DTIC at 400 mg m-2, 500 mg m-2 or 800 mg m-2. Each group also received fotemustine (100 mg m-2), 4 h after DTIC. The lowest extent of ATase depletion (highest nadir ATase) was seen in patients receiving 400 mg m-2. The mean nadir ATase, expressed as a percentage of pre-treatment ATase, was respectively 56.3%, 26.4% and 23.9% for 400 mg m-2, 500 mg m-2 and 800 mg m-2. The median nadir of ATase activity for pts receiving 800 mg m-2 pts was at 4-6 h and for pts given lower doses it was at 2-3 h. In addition, repeated measures analysis of variance of observations before chemotherapy, then at 2, 3, 4, 6 and 18 h after chemotherapy provides some evidence that ATase was depleted to a lesser extent after cycle 1 than after subsequent cycles (P = 0.025). It also provides evidence that the change in ATase activity over time varied with dose and cycle. The findings can be interpreted on the basis of a dosage-dependent metabolism of DTIC to an agent capable of methylation of DNA and subsequent depletion of PMC ATase: with higher DTIC doses, the extent of ATase depletion may be limited by the pharmacokinetics of DTIC metabolism. PMC ATase was measured in another group of 8 pts at various times after receiving only fotemustine (100 mg m-2) and in contrast to DTIC, no ATase depletion was seen suggesting that insufficient concentrations of fotemustine and/or its metabolites were available to react with DNA to produce a depletion of PMC ATase activity.
越来越多的实验证据表明，O6-烷基鸟嘌呤-DNA烷基转移酶（ATase）的内源性表达是细胞对包括达卡巴嗪（DTIC）在内的某些化疗药物产生耐药性的主要因素。我们最近发现，外周血单个核细胞（PMC）中ATase在DTIC作用后的消耗及随后的再生存在广泛的个体差异，现在已进一步研究这种消耗是否与所用DTIC的剂量以及化疗的重复治疗周期有关。在三组25例患者中，于接受400mg/m²、500mg/m²或800mg/m²的DTIC后长达24小时测量ATase水平。每组患者在DTIC给药4小时后还接受福莫司汀（100mg/m²）。接受400mg/m²DTIC的患者中，ATase消耗程度最低（最低点ATase最高）。以治疗前ATase的百分比表示，400mg/m²、500mg/m²和800mg/m²组的平均最低点ATase分别为56.3%、26.4%和23.9%。接受800mg/m²DTIC的患者中，ATase活性的中位数最低点出现在4 - 6小时，而接受较低剂量的患者则出现在2 - 3小时。此外，对化疗前以及化疗后2、3、4、6和18小时的观察结果进行重复测量方差分析，结果表明，与后续周期相比，第1周期后ATase的消耗程度较小（P = 0.025）。这也表明ATase活性随时间的变化因剂量和周期而异。这些发现可以基于DTIC向能够使DNA甲基化并随后消耗PMC中ATase的物质的剂量依赖性代谢来解释：DTIC剂量越高，ATase消耗的程度可能受DTIC代谢的药代动力学限制。在另一组8例患者中，仅接受福莫司汀（100mg/m²）后在不同时间测量PMC中的ATase，与DTIC不同，未观察到ATase消耗，这表明福莫司汀及其代谢产物的浓度不足以与DNA反应以导致PMC中ATase活性降低。
