Cytocidal Therapy In Vivo for Drug-Resistant Tumors

描述（由申请人提供）：转移性乳腺癌的化学治疗由于不能杀死耐药乳腺癌细胞而被阻止，因为它们的凋亡细胞死亡途径通常被阻断。此外，导致坏死细胞死亡的ATP的严重减少没有实现，因为单独的化疗仅适度降低耐药细胞中的ATP水平。然而，一种新的方法-联合给予多种ATP消耗剂与化疗q 2周x 3-进一步将ATP降低到癌细胞杀伤水平，产生耐药的部分肿瘤消退，体内毒性最小。同时阻断多个ATP产生途径对于在体内条件下达到杀死癌细胞所需的非常严重的ATP消耗程度是必要的，因为ATP是由多个代谢途径产生的。选择性的发生是因为肿瘤比正常组织对ATP消耗更敏感，因为肿瘤产生更多的ATP并消耗（消耗）更多的ATP。目的1比较不同无毒的5-和6-元ATP耗竭组合治疗的部分肿瘤消退（PR）率，以确定对耐药乳腺癌异种移植物的治疗“最佳”。目的2评价体内治疗肿瘤的最低ATP水平与PR率的相关性，作为“原理证明“。“目标3评估治疗诱导细胞死亡的主要模式。目的4评价长期治疗效果（治愈？）Aim 1的最佳细胞毒性诱导治疗在一年内耐药异种移植作为指导适当的临床试验。在临床中，由于抗癌药物的使用剂量为通常临床剂量的一半，因此应在明显减少毒副作用的情况下获得增强的治疗效果。如果临床验证，拟议的疗法将为治愈转移性乳腺癌开辟道路，治疗策略可能适用于其他耐药类型的癌症。

DESCRIPTION (provided by applicant): Chemotherapeutic cure of metastatic breast cancer is prevented by the inability to kill drug-resistant breast cancer cells because their apoptosis cell death pathway is usually blocked. Also, the severe reduction of ATP that causes necrosis cell death is not achieved since chemotherapy alone only modestly reduces ATP levels in drug-resistant cells. However, a new approach---co-administration systematically of multiple ATP-depleting agents with chemotherapy q 2 weeks x 3---further reduces the ATP to cancer cell-killing levels that produces drug-resistant partial tumor regressions with minimal toxicity in vivo. Concomitant blockade of multiple ATP-producing pathways is necessary to attain the very severe degree of ATP depletion necessary to kill cancer cells under in vivo conditions because ATP is generated by multiple metabolic pathways. Selectivity occurs because tumors are more sensitive to ATP depletion than normal tissues since tumors make more ATP and consume (deplete) more ATP. Aim 1 compares partial tumor regression (PR) rates treated by different non-toxic 5- and 6-member ATP-depleting combinations to determine the therapeutically "best" against drug-resistant breast cancer xenografts. Aim 2 evaluates nadir ATP levels in tumors treated in vivo by the "best" for correlation with PR rates as "proof-of-principle." Aim 3 evaluates the primary mode of treatment-induced cell death. Aim 4 evaluates the long-term therapeutic effects (cures?) of Aim 1's optimal cytocidal-inducing treatment over a one year period in drug-resistant xenografts as a guide to appropriate clinical trial. In the clinic, enhanced therapeutic efficacy should be obtained with markedly fewer toxic side- effects since the anticancer agents are employed at half the usual clinical dose. If validated clinically, the proposed therapy will open the way for cure of metastatic breast cancer, and the therapeutic strategy likely will apply to other drug-resistant types of cancer.