Nagarkatti M, Toney D M, Nagarkatti P S
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061.
Cancer Res. 1989 Dec 1;49(23):6587-92.
Chemotherapeutic efficacies of the nitrosoureas 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), chlorozotocin (CLZ), and streptozotocin (STZ) were investigated against the LSA tumor which is syngeneic to C57BL/6 mice. It was observed that a single injection of 20 mg/kg body weight of BCNU or CLZ, even at an advanced stage of tumor growth, completely cured greater than 90% of the tumor-bearing mice. Furthermore, BCNU-cured or CLZ-cured mice could specifically reject secondary rechallenge with the LSA tumor. In contrast, a single dose treatment with STZ at 20-200 mg/kg body weight failed to cure the tumor-bearing mice (0% survival). The failure of STZ to cure tumor-bearing mice was next addressed considering three possible mechanisms: (a) STZ was less tumoricidal; (b) STZ suppressed the immunity of the host; and (c) STZ failed to eliminate tumor-specific suppressor T-cells. The failure of STZ to cure tumor-bearing mice was not totally related to its tumoricidal properties since STZ at higher doses did possess significant tumoricidal activity in vitro and in vivo, comparable to that of BCNU or CLZ. When spleen cells from normal mice treated with BCNU, CLZ, or STZ were assayed for their responsiveness to the T-cell mitogens concanavalin A or phytohemagglutinin, it was observed that STZ was in fact less immunosuppressive than BCNU or CLZ. The fact that STZ did not suppress the immunity of the host was also suggested by the findings that BCNU-cured mice treated with STZ or CLZ could still reject secondary rechallenge with the specific tumor LSA. Following treatment of tumor-bearing mice with BCNU or CLZ, tumor-specific delayed type hypersensitivity responses were demonstrable in these mice but not in STZ-treated mice. The inability of STZ-treated tumor-bearing mice to elicit a delayed type hypersensitivity response was not due to selective depletion of delayed type hypersensitivity-inducing CD4+ T-cells but was probably due to failure of STZ to eliminate tumor-specific suppressor cells. Together these findings suggested that the failure of STZ to cure LSA tumor-bearing mice was not due to lack of tumoricidal activity or related to suppression of tumor-specific effector T-cell function but may be due to the failure of STZ to eliminate tumor-specific T suppressor cells. The present study suggests that the outcome of chemotherapy with nitrosoureas depends, in addition to the tumoricidal activity of the drug, on the immunomodulating action on the immune mechanisms of the host.
研究了亚硝基脲类药物1,3-双(2-氯乙基)-1-亚硝基脲(BCNU)、氯脲霉素(CLZ)和链脲佐菌素(STZ)对与C57BL/6小鼠同基因的LSA肿瘤的化疗效果。观察到，即使在肿瘤生长的晚期，单次注射20mg/kg体重的BCNU或CLZ，也能使超过90%的荷瘤小鼠完全治愈。此外，经BCNU或CLZ治愈的小鼠能够特异性排斥LSA肿瘤的二次再攻击。相比之下，单次给予20-200mg/kg体重的STZ未能治愈荷瘤小鼠(生存率为0%)。接下来，考虑三种可能的机制探讨了STZ未能治愈荷瘤小鼠的原因：(a) STZ的杀肿瘤活性较低；(b) STZ抑制宿主免疫；(c) STZ未能消除肿瘤特异性抑制性T细胞。STZ未能治愈荷瘤小鼠并非完全与其杀肿瘤特性有关，因为高剂量的STZ在体外和体内确实具有显著的杀肿瘤活性，与BCNU或CLZ相当。当检测用BCNU、CLZ或STZ处理的正常小鼠的脾细胞对T细胞有丝分裂原刀豆球蛋白A或植物血凝素的反应性时，发现STZ实际上比BCNU或CLZ的免疫抑制作用更小。用STZ或CLZ处理的经BCNU治愈的小鼠仍能排斥特异性肿瘤LSA的二次再攻击，这一发现也表明STZ不会抑制宿主免疫。在用BCNU或CLZ处理荷瘤小鼠后，这些小鼠可出现肿瘤特异性迟发型超敏反应，而经STZ处理的小鼠则未出现。经STZ处理的荷瘤小鼠无法引发迟发型超敏反应，并非由于迟发型超敏反应诱导性CD4+ T细胞的选择性耗竭，而可能是由于STZ未能消除肿瘤特异性抑制细胞。这些发现共同表明，STZ未能治愈LSA荷瘤小鼠并非由于缺乏杀肿瘤活性或与抑制肿瘤特异性效应T细胞功能有关，而可能是由于STZ未能消除肿瘤特异性T抑制细胞。本研究表明，亚硝基脲类药物化疗的结果除了取决于药物的杀肿瘤活性外，还取决于对宿主免疫机制的免疫调节作用。
