Mokyr M B, Brundrett R B, Colvin M, Dray S
Cancer Res. 1986 Jul;46(7):3313-20.
We have previously shown that mice bearing a late-stage, large primary MOPC-315 plasmacytoma and extensive metastases can be cured by a low dose of the bifunctional alkylating drug, cyclophosphamide (BiCY) (J.C.D. Hengst et al., Cancer Res., 40: 2135-2141, 1980). Here we show that therapy with the monofunctional form of cyclophosphamide (MoCY) can also cure such mice. However, a dose of at least 150 mg of MoCY per kg is required to approximate the curative effectiveness of the lowest curative dose of BiCY, i.e., 15 mg/kg. This need for a 10-fold higher dose of MoCY is due, at least in part, to the 10-fold lower direct tumoricidal and/or tumoristatic activity of MoCY compared to BiCY. Consequently, a 10-fold higher dose of MoCY is required to directly reduce the tumor burden to the level reduced by 15 mg of BiCY per kg. Other than dose, the therapy of the mice with 150 mg of MoCY per kg was similar in its essential features to that shown previously for therapy with 15 mg of BiCY per kg (J.C.D. Hengst et al., Cancer Res., 40: 2135-2141, 1980; J.C.D. Hengst et al., Cancer Res., 41:2163-2167, 1981; Q-W. Ye et al., Cancer Immunol. Immunother., 16:162-169, 1984; Q-W. Ye and M.B. Mokyr, Cancer Res., 44: 3873-3879, 1984; M.B. Mokyr and S. Dray, Cancer Res., 43: 3112-3119, 1983), namely: (a) the drug does not directly eradicate all tumor cells; (b) host T-cell-dependent antitumor immunity is also required for the curative effect; (c) the therapy of tumor bearers leads to the rapid appearance of an augmented antitumor immune potential in their hitherto immunosuppressed spleen; and (d) the cured mice are resistant to a subsequent challenge with at least 300-fold the minimal lethal tumor dose. Thus, cross-linking is not an essential property for the immunomodulatory activity of BiCY nor for its direct antitumor effect. However, in the presence of cross-linking activity, a much lower dose of drug is effective.
我们之前已经表明，携带晚期、大型原发性MOPC - 315浆细胞瘤并伴有广泛转移的小鼠，可通过低剂量的双功能烷化剂环磷酰胺（BiCY）治愈（J.C.D. Hengst等人，《癌症研究》，40: 2135 - 2141, 1980）。在此我们表明，用单功能形式的环磷酰胺（MoCY）进行治疗也能治愈此类小鼠。然而，每千克体重至少需要150毫克的MoCY才能达到最低治愈剂量的BiCY（即15毫克/千克）的治愈效果。MoCY需要高10倍剂量的原因，至少部分是由于与BiCY相比，MoCY的直接杀肿瘤和/或抑肿瘤活性低10倍。因此，需要高10倍剂量的MoCY才能将肿瘤负荷直接降低到每千克15毫克BiCY所降低的水平。除剂量外，每千克体重用150毫克MoCY治疗小鼠的基本特征与之前每千克体重用15毫克BiCY治疗的情况相似（J.C.D. Hengst等人，《癌症研究》，40: 2135 - 2141, 1980；J.C.D. Hengst等人，《癌症研究》，41: 2163 - 2167, 1981；Q - W. Ye等人，《癌症免疫与免疫治疗》，16: 162 - 169, 1984；Q - W. Ye和M.B. Mokyr，《癌症研究》，44: 3873 - 3879, 1984；M.B. Mokyr和S. Dray，《癌症研究》，43: 3112 - 3119, 1983），即：（a）药物不能直接根除所有肿瘤细胞；（b）治愈效果还需要宿主T细胞依赖性抗肿瘤免疫；（c）对荷瘤小鼠的治疗会使其此前免疫抑制的脾脏中迅速出现增强的抗肿瘤免疫潜能；（d）治愈的小鼠对随后至少300倍最小致死肿瘤剂量的攻击具有抗性。因此，交联对于BiCY的免疫调节活性及其直接抗肿瘤作用而言并非必需特性。然而，在存在交联活性的情况下，更低剂量的药物就有效。
