MECHANISM OF MELPHALAN-MEDIATED TUMOR ERADICATION

总的来说，拟议的研究旨在获得信息， 应该可以描绘出肿瘤的一些特征 低剂量的美法仑在晚期阶段是有疗效的系统， 肿瘤生长 我们已经知道，低剂量的治疗效果 携带大MOPC-315浆细胞瘤的小鼠的美法仑剂量取决于 抗肿瘤免疫在肿瘤根除中的作用。 我们将 确定低剂量的美法仑是否也能治愈小鼠 一种选择性浆细胞瘤的大肿瘤， 免疫原性，从而引发不同程度的抗肿瘤免疫， 有助于肿瘤根除。 对于每一个肿瘤，我们将 建立剂量反应曲线，以确定美法仑的最低剂量 这对处于肿瘤生长晚期的小鼠是有疗效的。 肿瘤 低剂量美法仑在晚期具有治愈性的模型 肿瘤生长的影响，我们将确定 低剂量的药物仅仅是由于药物的杀肿瘤活性，或 T细胞依赖的抗肿瘤免疫是否也有助于肿瘤 根除 在肿瘤模型中，低剂量的美法仑不能 在肿瘤生长的晚期阶段，我们将确定是否 低剂量化疗未能治愈这些小鼠是由于 肿瘤细胞的相对抗性（与MOPC-315相比 细胞）对药物的直接毒性作用和/或由于 抗肿瘤免疫水平不足以控制 在药物从肿瘤细胞中清除后残留的肿瘤负荷 流通 从拟议研究中收集的信息应 使得描绘肿瘤系统的某些特征成为可能 其中可能利用宿主抗肿瘤免疫 治疗上 （高频）

In general, the proposed research is aimed at obtaining information that should make it possible to delineate some of the characteristics of a tumor system in which a low dose of melphalan is curative at an advanced stage of tumor growth. We know already that the curative effectiveness of a low dose of melphalan for mice bearing a large MOPC-315 plasmacytoma depends on the contribution of antitumor immunity in tumor eradication. We will determine whether a low dose of melphalan is curative also for mice bearing a large tumor of selected plasmacytomas that differ in their immunogenicity, thus eliciting varying degrees of antitumor immunity that can contribute to tumor eradication. For each of these tumors, we will establish a dose-response curve to determine the lowest dose of melphalan that is curative for mice at an advanced stage of tumor growth. In tumor models for which a low dose of melphalan is curative at an advanced stage of tumor growth, we will determine whether the curative effectiveness of the low dose of drug is due solely to the drug's tumoricidal activity or whether T-cell-dependent antitumor immunity also aids in tumor eradication. In tumor models for which a low dose of melphalan is not curative at an advanced stage of tumor growth, we will determine whether the failure of the low-dose chemotherapy to cure such mice is due to relative resistance of the tumor cells (as compared with the MOPC-315 cells) to the direct toxic effects of the drug and/or due to the development of an insufficient level of antitumor immunity to control the tumor burden that remains after clearance of the drug from the circulation. The information gathered from the proposed studies should make it possible to delineate some of the characteristics of a tumor system in which it might be possible to exploit host antitumor immunity therapeutically. (HF)