Kyrtopoulos S A, Souliotis V L, Valavanis C, Boussiotis V A, Pangalis G A
National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Athens, Greece.
Environ Health Perspect. 1993 Mar;99:143-7. doi: 10.1289/ehp.9399143.
O6-Methylguanine has been measured in peripheral blood leukocytes of 14 patients during one or more cycles of treatment with procarbazine (daily treatment for 10 days) and in 12 patients during one or more cycles of treatment with dacarbazine (single dose per cycle). Adduct formation at levels up to about 0.4 fmole/microgram DNA was detected in all procarbazine- and all but one dacarbazine-treated patients at some point after treatment. O6-Methylguanine accumulated during procarbazine treatment in a dose-related manner (mean rate of accumulation 2.8 x 10(-4) fmole/microgram DNA per mg/m2 dose) and appeared to approach a plateau by the end of the cycle (above 600 mg/m2 cumulative dose). The average rate of O6-methylguanine formation 2 hr after dacarbazine treatment was 11 +/- 8 x 10(-4) fmole/microgram DNA per mg/m2 dose. Individuals examined on more than one treatment cycle with either drug showed broadly similar methylation responses. The rate of adduct accumulation showed a nonsignificant, negative correlation with the pretreatment lymphocyte levels of the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) in the case of procarbazine and no correlation in the case of dacarbazine. No consistent lymphocyte AGT depletion was noted as a result of treatment with either drug. No correlation between O6-methylguanine formation and hematological toxicity was observed. In eight patients showing full remission after treatment with dacarbazine, the value of O6-methylguanine (averaged over all the cycles) was 0.252 +/- 0.120 fmole/microgram DNA while in four patients showing partial or no response it was 0.087 +/- 0.110 fmole/microgram DNA (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
在14例接受丙卡巴肼治疗（每日治疗10天，一个或多个疗程）的患者外周血白细胞中以及12例接受达卡巴嗪治疗（每个疗程单剂量）的患者外周血白细胞中检测到了O6-甲基鸟嘌呤。在所有接受丙卡巴肼治疗的患者以及除1例之外的所有接受达卡巴嗪治疗的患者中，在治疗后的某个时间点均检测到了加合物形成，其水平高达约0.4飞摩尔/微克DNA。在丙卡巴肼治疗期间，O6-甲基鸟嘌呤以剂量相关的方式积累（平均积累速率为每毫克/平方米剂量2.8×10⁻⁴飞摩尔/微克DNA），并且在疗程结束时（累积剂量超过600毫克/平方米）似乎接近平台期。达卡巴嗪治疗后2小时，O6-甲基鸟嘌呤形成的平均速率为每毫克/平方米剂量11±8×10⁻⁴飞摩尔/微克DNA。接受两种药物多次治疗周期检查的个体显示出大致相似的甲基化反应。在丙卡巴肼治疗中，加合物积累速率与修复酶O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）的预处理淋巴细胞水平呈非显著负相关，而在达卡巴肼治疗中则无相关性。未观察到因两种药物治疗导致一致的淋巴细胞AGT耗竭。未观察到O6-甲基鸟嘌呤形成与血液学毒性之间的相关性。在8例接受达卡巴嗪治疗后完全缓解的患者中，O6-甲基鸟嘌呤的值（所有疗程的平均值）为0.252±0.120飞摩尔/微克DNA，而在4例部分缓解或无反应的患者中为0.087±0.110飞摩尔/微克DNA（p<0.05）。（摘要截断于250字）
