MECHANISM OF MELPHALAN-MEDIATED TUMOR ERADICATION

本提案的主要目的是了解 一种广泛使用的抗癌药物美法仑（L- PAM）;将平衡从免疫抑制转移到强效 抗肿瘤免疫，当给予小鼠在先进的 肿瘤生长的阶段。 我们已经知道， 低剂量该烷化剂免疫调节活性 在一些浆细胞瘤肿瘤模型中，不仅包括 抑制细胞活性的消除，但也诱导 在T细胞中出现免疫增强活性， 共表达Lyt 2和L3 T4抗原，即使这些细胞 存在于次级淋巴器官中。 实验将 进行，以确定胸腺在外观中的作用， 具有这种不寻常表型的T细胞（即，表达 同时Lyt 2和L3 T4抗原）， 低剂量给药后不久， 化疗，因为（a）大于或等于80%的 胸腺内的淋巴细胞共表达两种标记物，和（B） 低剂量L-PAM治疗使来自MOPC-315的胸腺细胞 荷瘤小鼠（但不是来自正常小鼠）能够 导致产生增强的抗肿瘤细胞毒性， 当加入到正常脾细胞的免疫培养物中时 和“原生”肿瘤 此外，我们将阐明 低剂量化疗对细胞成分的影响 肿瘤携带者胸腺。 作为这项研究的一部分，我们将 免疫学上确定Lyt 2和L3 T4表型 L-PAM处理的MOPC-315肿瘤的胸腺中的“活性”细胞 并阐明了低剂量的机制， L-PAM使来自MOPC-315肿瘤携带者的胸腺细胞 免疫“活跃”。 此外，我们将确定 这些“活跃的”胸腺细胞产生 产生增强的裂解活性。 重点将放在 将我们的观察扩展到其他肿瘤模型。 为此 为了达到这个目的，我们将选择不同的浆细胞瘤， 其免疫原性。 因此，从这些获得的结果 实验还将提供有关 肿瘤细胞免疫原性和随后的 低剂量L-PAM疗法诱导“活性”的出现 荷瘤小鼠胸腺中的细胞。 最后我们将 确定胸腺对治疗的重要性 MOPC-315或MOPC-315低剂量L-PAM治疗的有效性 104 E肿瘤携带者，因为这种治疗有效性 治疗方案取决于T细胞依赖性免疫应答的能力。 抗肿瘤免疫，以消除大量致瘤负荷 药物从循环中清除后残留的。

The main objective of this proposal is to understand the mechanism by which a widely used anticancer drug, melphalan (L- PAM); shifts the balance from immunosuppression to potent antitumor immunity when administered to mice at an advanced stage of tumor growth. We know already that the immunomodulatory activity of a low dose of this alkylating agent consists, in some plasmacytoma tumor models, not only of elimination of suppressor cell activity, but also of induction of appearance of immunopotentiating activity in T-cells that coexpress the Lyt 2 and the L3T4 antigens even when these cells reside in secondary lymphoid organs. Experiments will be performed to determine the role of the thymus in the appearance of T cells with such an unusual phenotype (i.e., expressing simultaneously the Lyt 2 and L3T4 antigens) in the spleens of adult tumor-bearing mice shortly after the low dose chemotherapy since (a) greater than or equal to 80% of the lymphocytes within the thymus coexpress both markers, and (b) the low dose L-PAM therapy renders thymocytes from MOPC-315 tumor-bearing mice (but not from normal mice) capable of bringing about the generation of enhanced antitumor cytotoxicity when added to the immunization culture of normal spleen cells and the "autochthonous" tumor. In addition, we will elucidate the effect of the low dose chemotherapy on the cellular composition of the tumor bearer thymus. As part of this study, we will determine the Lyt2 and L3T4 phenotype of the immunologically "active" cells in the thymus of L-PAM treated MOPC-315 tumor bearers as well as elucidate the mechanism by which the low dose L-PAM renders thymocytes from MOPC-315 tumor bearers immunologically "active". In addition, we will determine the mechanism by which these"active" thymocytes bring about the generation of enhanced lytic activity. Emphasis will be placed on extending our observations to other tumor models. For this purpose, we will employ selected plasmacytomas that differ in their immunogenicity. Thus, the results obtained from these experiments will also provide information as to the correlation between tumor cell immunogenicity and the subsequent ability of low dose L-PAM therapy to induce the appearance of "active" cells in the thymus of tumor-bearing mice. Finally, we will determine the importance of the thymus to the curative effectiveness of low dose L-PAM therapy of MOPC-315 or MOPC- 104E tumor bearers since the therapeutic effectiveness of this therapeutic protocol depends on the ability of T-cell-dependent antitumor immunity to eradicate a large tumorigenic load remaining after clearance of the drug from the circulation.