CHEMOTHERAPEUTIC STUDIES IN SOLID TUMORS

在修订的实体肿瘤项目中，我们提出了新的治疗方法的研究 适用于非血液系统恶性肿瘤。每一种疾病都是一个模型 用于测试可能与和相关的概念的系统 随后在其他具有相似生物学特性的实体肿瘤中进行测试。五 具体目标集中在新药、改进的药物和放射治疗上 分娩和基因突变作为预后因素。在具体目标1中， 为乳腺癌和细菌患者建议的大剂量方案 细胞瘤。由于这两种肿瘤对几种药物都有反应 不同的抗肿瘤类别，他们是优秀的模型系统 用来检验高剂量理论的假设和茎的新方法 细胞重组。在特定的目标2中，我们将确定抗肿瘤 针对肿瘤特异性“靶点”的药物组合的活性 外加传统的细胞毒性药物。最初将对两种药物进行研究。 第一，抑制结合生长的单抗225 表皮生长因子受体的因子配体，抑制 依赖该受体生长的肿瘤中的增殖 在体内外与细胞毒药物有协同作用。第二， 放射性药物186Re-HEDP靶向肿瘤诱导的新骨 骨转移瘤的形成，并将结合 前列腺癌患者的化疗。在具体目标3中， 将测试维甲酸和其他新药的抗肿瘤活性， 在传统的第二阶段和随机试验中都是如此。在具体目标4中， 三维治疗计划将用于提供放射治疗 以更高的精确度和更少的局部组织 毒副作用与化疗相结合。最初的目标是改进 众所周知，局部晚期非小细胞肺癌的局部控制 与当地相当大的死亡率和发病率有关 复发性疾病。在具体目标5中，基因之间的关联 TP53和RB1的改变以及反应和存活率将在 乳腺癌、头颈癌(以TP53为例)和膀胱癌 (适用于TP53和RB1)。正如我们在I(12P)的情况下所展示的那样， 生殖细胞肿瘤的标记染色体，肿瘤中的遗传缺陷可以 在治疗选择中作为诊断和预后的工具是有用的。之后 在第二阶段试验、第三阶段试验中的优化治疗将是 在其他相关肿瘤系统中进行和应用的概念。

In the revised Solid Tumor Project, we propose studies of new treatment for the non-hematologic malignancies. Each disease serves as a model system in which to test a concept which may have relevance to and subsequently be tested in other solid tumors with a similar biology. Five specific aims focus on new drugs, improved drug and radiation therapy delivery, and genetic mutations as prognostic factors. In Specific Aim 1, high-dose programs as proposed for patients with breast cancer and germ cell tumors. Since these two tumors are responsive to several drugs in different antineoplastic classes, they are excellent model systems in which to test the hypotheses of high-dose theory and new methods of stem cell reconstitution. In Specific Aim 2, we will determine the antitumor activity of combinations of an agent directed at a tumor-specific "target plus traditional cytotoxic drugs. Two agents will be studied initially. First, monoclonal antibody 225, which inhibits the binding of growth factor ligands to the epidermal growth factor receptor, inhibits proliferation in tumors which are dependent on this receptor for growth and is synergistic with cytotoxic drugs in vitro and in vivo. Second, the radiopharmaceutical 186Rhenium-HEDP targets tumor-induced new bone formation in bone metastases and will be studied in combination with chemotherapy in patients with prostate cancer. In Specific Aim 3, the antineoplastic activity of retinoids and other new drugs will be tested, both in traditional Phase II and in randomized trials. In Specific Aim 4, 3-dimensional treatment planning will be used to deliver radiation therapy to the tumor volume with greater precision and lesser local tissue toxicity in combination with chemotherapy. The initial goal is to improve local control of locally advanced non-small cell lung cancer, well-known to be associated with considerable mortality and morbidity from locally recurrent disease. In Specific Aim 5, the association between genetic alterations in TP53 and RB1 and response and survival will be studied in breast and head and neck cancer (in the case of TP53) and bladder cancer (for both TP53 and RB1). As we have demonstrated in the case of i(12p), the marker chromosome for germ cell tumors, genetic defects in tumors can be useful as diagnostic and prognostic tools in treatment selection. After optimization of treatment in Phase II trials, Phase III trials will be conducted and concepts applied in other relevant tumor systems.