Cyclophosphamide와 Paclitaxel 항암치료 시 GnRH agonist I, II 및 GnRH antagonist 투여에 의한 생쥐난포 보존효과
Preservation of ovarian follicle by concomitant administration of GnRH agonist I, II or GnRH antagonist during Cyclophosphamide or Paclitaxel chemotherapy in mice
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목적: 생쥐에서 cyclophosphamide와 paclitaxel의 용량에 따른 원시난포의 파괴정도와 일시적으로 난소를 억제시켜 항암제의 세포독성을 회피하는 GnRHa I과 II 그리고 GnRH antagonist를 병행 투여하여 각기 다른 용량에서 원시난포의 보존효과를 알아보기 위하여 실험하였다. 연구 방법: 생쥐에 각각 50 mg/kg, 75 mg/kg의 cyclophosphamide와 12.5 mg/kg, 19 mg/kg의 paclitaxel을 투여하여 대조군과 비교하여 원시난포의 파괴 정도와 세포자멸사 지표를 측정하였다. 또한 GnRHa I, GnRH antagonist 그리고 GnRHa II를 각각 0.1 mg/kg을 병용투여해서 원시난포의 증가정도와 세포자멸사지표의 감소정도를 측정하였다. 결과: 원시난포의 경우 cyclophosphamide와 paclitaxel의 저용량에서 GnRHa I, II, GnRH antagonist 모두 원시난포 보존효과가 있었고 고용량에서는 GnRH antagonist에서만 보존효과가 있었다. 효과가 있었던 GnRH analogues 각 군 간의 차이는 없었다. 세포자멸사 지표에서는 cyclophosphamide, paclitaxel의 저용량, 고용량 모두에서 GnRHa I, II 및 GnRH antagonist 투여 시 감소하였다. 저용량에서 GnRH analogues 각 군 간의 비교에서는 GnRHa I이 가장 효과적 이었다. 결론: GnRH analogue의 병행투여 군에서 통계적인 유의성을 보인 것으로 보아 항암치료를 받는 가임여성에서도 비슷한 효과를 기대할 수 있으며 이를 뒷받침할 임상연구가 필요할 것으로 생각된다.
Abstract
Objective: The degree of destruction of primordial follicles was investigated following the administration of cyclophosphamide or paclitaxel respectively in mouse ovaies. And then the effect of GnRHa I, GnRH antagonist and GnRHa II on the primordial follicles was evaluated following the administration of cyclophosphamide or paclitaxel. Methods: Saline or cyclophosphamide (50 mg/kg or 75 mg/kg) were intraperitoneally injected into seven-week old female ICR mice. GnRHa I (Leuplin®), GnRH antagonist (Cetrotide®) or GnRHa II (H-6038) was injected into mice, and administered with 50 mg/kg and 75 mg/kg of cyclophosphamide following 9 days treatment with GnRH analogues. After collecting ovaries, H&E staining was performed and the number of primordial follicles was counted. To confirm the induction of apoptosis, TUNEL assay was performed. Another experimental groups of mice were administered with a low concentration (12.5 mg/kg) or a high concentraion (19 mg/kg) of paclitaxel. Results: Cyclophosphamide and paclitaxel cause mild to moderate destruction of primordial follicles in mouse ovaries. The number of primordial follicles in the group of high dose was noted less than in that of low dose treated with cyclophosphamide or paclitaxel. Increased the apoptotic indices were shown in the group of cyclophosphamide or paclitaxel compared to in saline only treated group. Treatment with GnRHa I, GnRH antagonist and GnRHa II significantly increased the number of primordial follicles at a low concentration of cytotoxic agents (P<0.05), whereas the number of primoridal follicle increased only in GnRHa I antagonist treated group at a high concentration of cyclophosphamide or paclitaxel (P<0.05). Conclusion: The present study shows that GnRH analogues alleviate destruction of primordial follicles caused by cyclophosphamide and paclitaxel in mouse ovaries, suggesting that GnRH analogues may be applicable to increase fertility opportunity in malignant cancer patients of reproductive age planning future pregnancies.
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