항암제 투여가 인체 백혈구에 미치는 영향에 관한 세포유전학적 연구

Abstract

항암제는 대부분 DNA의 염기쌍과 작용하여 핵산의 합성을 방해함으로서 항암작용을 하는 것으로 암세포에 치사작용 이외에도 정상세포에 손상을 주어 약물에 의한 세포분열과 증식의 억제, 혹은 염색체 이상을 초래할 수 있는 것으로 알려져 있다. 각종 악성 종양의 치료에 사용되고 있는 cis-dichlorodiammine platinumII(이하 cis-DDP로 약칭), cyclophosphamide, adriamycin은 단독 또는 복합적으로 암치료에 효과적으로 널리 사용되고 있다. 이들 항암제가 인체 백혈구에 미치는 영향을 검토하기 위해서 in vitro에서 건강한 성인 여자 5명을 대상으로 채혈하여 cis-DDP, cyclophosphamide, adriamycin을 각각의 농도별로 투여한 후 배양하고, in vivo에서 상기의 항암제로 치료받은 암환자 27명과 대조군 2명(항암제 치료나 방사선 조사를 받은 경험이 없는 난소암 환자)의 혈액을 배양하였으며, 각 실험군에서 자매 염색분체 교환(Sister Chromatid Exchange : 이하 SCE로 약칭) 검사법과 염색체 이상 검사법을 이용하여 염색체 변이를 비교 분석한 결과는 다음과 같다. 1. In vitro에서 cis-DDP와 adriamycin 각각의 농도가 증가할수록 세포분열 작용이 강하게 억제 되었다. 반면 cyclophosphamide는 대조군에 비해 세포분열 게수(mitotic index)가 다소 낮았으나 농도에 따른 차이는 발견할 수 없었다. 2. In vitro에서 cis-DDP와 adriamycin 각각의 농도가 증가할수록 SCE 빈도 및 염색체 이상 빈도가 유의적으로 증가하였으며, SCE 빈도는 대조군에 비해 각 염색체 군(A-G군)에서 모두 증가하였다. 염색체 이상형 중에서 교환형(exchange figure)은 cis-DDP투여군에서는 1.00μg/ml 이상의 농도에서, adriamycin 투여군에서는 0.05 μg/ml 이상의 농도에서 관찰되었다. 3. In vivo에서 cis-DDP, cis-DDP/adriamycin 및 cis-DDP/cyclophosphamide/adriamycin 치료군의 치료후 SCE빈도 및 염색체 이상 빈도는 치료 전에 비해 모두 높았으며, 이중 cis-DDP/cyclophosphamide/adriamycin 치료군에서 가장 높았고, 다음이 cis-DDP/adriamycin, cis-DDP 순서로 나타났다. 4. 염색체 이상형은 염색분체 열극, 염색분체 절단, 염색체 열극, 염색체 절단, dicentric, ring, 교환 등이었으며, 교환형은 cis-DDP 단독 치료군에서 전혀 관찰되지 않은 반면, cis-DDP/cyclophosphamide/adriamycin 치료군이 cis-DDP/adriamycin 치료군보다 많이 관찰되었다. 5. 두가지 이상의 항암제로 복합 연속 치료를 받은 4명중 3명에서 치료 2~5주후 SCE 빈도는 암환자 대조군과 비슷한 수준으로 회복되었으나, 염색체 이상 빈도는 여전히 높게 나타났다. 또한 치료 횟수가 증가할수록 치료 후의 SCE 빈도 및 염색체 이상 빈도는 증가하는 경향을 나타내었다.

; It is Known that most cytotoxic drugs have the potential of not only killingcancer cells by many of them impairing synthesis of nucleic acids by reacting with certain DNA bases but also resulting in inevitable damages to normal cells through more or less similar mechanisms, thus invoking suppression of cell division and proliferation, or even chromosomal aberration. Cis-dichlorodiammine platinum II (cis-DDP), cyclophosphamide, adriamycin are only the several anticancer drugs employed, singly or in combination, in the treatment of various malignant neoplasms. This study was initiated to evaluate the effects of these anticancer drugs on human lymphocyte. Peripheral blood samples drawn from five healthy woman volunteers were treated, in vitro, with several concentration of cis-DDP, cyclophosphamide, and adriamycin, respectively, and incubated. Also, peripheral bloods from twenty-seven cancer patients treated with these chemotherapeutic agents and two control patients, with ovarian cancer with no prior history of anticancer chemotherapy nor irradiation were incubated. Using the techniques of sister chromatid exchange (SCE) and chromosomal aberration, chromosome analysis in each group was made; the following results were obtained: 1. The degree of suppression of cell division by cis-DDP and adriamycin in vitro became pronounced with increasing concentration of each of these two drugs. Meanwhile, with cyclophosphamide, no significant effect was noted although mitotic index tended to be somewhat lower than that in control. 2. Incidence of SCE and chromosomal aberration increased significantly as the concentrations of cis-DDP and adriamycin in vitro each incremented. SCE incidence increased in all chromosome groups (A to G) compared with control. “Exchange figure” was observed with the concentration of cis-DDP from 1.00 μg/ml and that of adriamycin from 0.05 μg/ml in the group given cis-DDP and the group given adriamycin respectively. 3. Incidence of SCE and chromosomal aberration in vivo in the three groups, each treated with cis-DDP, cis-DDP and adriamycin, and cis-DDP, cyclophosphamide and adriamycin were all higher after than before treatment: it was the highest in the group given cis-DDP, cyclophosphamide and adriamycin, followed by the group given cis-DDP and adriamycin, then group given cis-DDP alone. 4. The types of chromosomal aberration encountered in patients treated with anticancer chemotherapy were “chromatid gap”, “chromatid break”, “chromosome gap”, “chromosome break”, “dicentric”, “ring”, and “exchange figure”. The exchange figure was not noted in the group treated with cis-DDP alone. However it was common in the group treated the regimen of cis-DDP, cyclophosphamide, and adriamycin; the incidence was higher than that noted in the group treated with cis-DDP and adriamycin. 5. Three of the four patients continually treated with at least two anticancer drugs showed a decline in the incidence of SCE two to five weeks following treatment compared with control. However, the high incidence of other chromosomal aberrations remained unchanged. Further, incidence of SCE and chromosomal aberration tended to increase with the number of cycles of treatment.