Pourtier-Manzanedo A, Didier A, Froidevaux S, Loor F
Laboratoire d'Immunologie-II, Faculté de Pharmacie, Université Louis Pasteur, Strasbourg, France.
Toxicology. 1995 May 23;99(3):207-17. doi: 10.1016/0300-483x(95)03056-l.
In the mouse, the P-glycoprotein-directed chemosensitizer SDZ PSC 833 could both restore a therapeutic window for doxorubicin against multidrug-resistant tumors, by inhibiting P-glycoprotein function, and increase the anti-cancer drug efficacy against drug-sensitive tumors, by increasing doxorubicin bioavailability. Since the success of such combined chemotherapy treatments might have been limited by the myelotoxicity of doxorubicin and the P-glycoprotein expression on some blood cells, their lymphotoxicity and myelotoxicity was studied on normal B6D2F1 mice, and whenever possible, the persistence of blood cell alterations was also searched for in scid recipients of lymphohaematopoietic grafts from the donor mice. Analyzed parameters were blood, lymphoid and myeloid cell numbers, proliferative responses to T- and B-cell mitogens, and serum immunoglobulin levels. Cell alterations caused by doxorubicin alone were potentiated by SDZ PSC 833, but did not persist in scid recipients. Chemotherapy regimens combining SDZ PSC 833 and doxorubicin, and known for their therapeutic benefit for multidrug-resistant tumor-bearing mice, only caused a rather mild toxicity for the lympho-myeloid system of normal mice.
在小鼠中，P-糖蛋白导向的化学增敏剂SDZ PSC 833既能通过抑制P-糖蛋白功能来恢复阿霉素针对多药耐药肿瘤的治疗窗口，又能通过提高阿霉素的生物利用度来增强抗癌药物对药物敏感肿瘤的疗效。由于此类联合化疗的成功可能受到阿霉素的骨髓毒性以及某些血细胞上P-糖蛋白表达的限制，因此在正常B6D2F1小鼠身上研究了它们的淋巴毒性和骨髓毒性，并且只要有可能，还在来自供体小鼠的淋巴造血移植的scid受体中寻找血细胞改变的持续性。分析的参数包括血液、淋巴细胞和髓细胞数量、对T细胞和B细胞有丝分裂原的增殖反应以及血清免疫球蛋白水平。单独使用阿霉素引起的细胞改变被SDZ PSC 833增强，但在scid受体中并未持续存在。将SDZ PSC 833和阿霉素联合使用的化疗方案，因其对携带多药耐药肿瘤的小鼠具有治疗益处而闻名，仅对正常小鼠的淋巴-髓系统造成相当轻微的毒性。
