MECHANISM OF MELPHALAN-MEDIATED TUMOR ERADICATION

一般而言，拟议的研究旨在获得以下信息 应该可以描绘出肿瘤的某些特征 一种小剂量的马法兰在晚期可治愈的系统。 肿瘤生长。我们已经知道，一种治疗效果较低的 马法兰对荷大型MOPC-315浆细胞瘤小鼠的剂量取决于 抗肿瘤免疫在肿瘤根除中的作用。我们会 确定小剂量的马法兰是否也能治愈小鼠 浆细胞瘤一种由精选的浆细胞瘤组成的大肿瘤，其肿瘤类型不同 免疫原性，从而引发不同程度的抗肿瘤免疫， 有助于根除肿瘤。对于每一个肿瘤，我们都会 建立剂量-反应曲线确定马法兰的最低剂量 这对处于肿瘤生长晚期的小鼠是有疗效的。在肿瘤中 小剂量马法兰可在晚期治愈的模型 对于肿瘤的生长，我们将决定其疗效是否 低剂量的药物完全是由于药物的杀瘤活性或 T细胞依赖的抗肿瘤免疫是否也有助于肿瘤 根除。在小剂量马法兰不能治疗的肿瘤模型中 治愈在肿瘤生长的晚期，我们将确定 小剂量化疗未能治愈这类小鼠是由于 肿瘤细胞的相对抗性(与MOPC-315比较 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，无法控制 药物清除后仍然存在的肿瘤负担 发行量。从拟议研究中收集的信息应 使描述肿瘤系统的一些特征成为可能 其中可能利用宿主抗肿瘤免疫 从治疗上讲。(Hf)

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)