Cytocidal Therapy In Vivo for Drug-Resistant Tumors

转移性乳腺癌的化疗治疗因无法杀死耐药乳房而无法治愈 癌细胞因为它们的凋亡细胞死亡途径通常是被阻断的。此外，严重减少了 导致坏死细胞死亡的ATP是无法实现的，因为单用化疗只能略微降低ATP 耐药细胞中的水平。然而，一种新的方法是系统地联合管理多个ATP- 化疗2周×3周的耗竭剂进一步降低了ATP对癌细胞的杀伤水平， 在体内产生具有抗药性的部分肿瘤消退，毒性最小。随之而来的封锁 要达到非常严重的ATP耗竭程度，必须有多条ATP产生途径 在体内条件下杀死癌细胞，因为三磷酸腺苷是由多条代谢途径产生的。 选择性的发生是因为肿瘤比正常组织对ATP的耗尽更敏感 制造更多的ATP，消耗(消耗)更多的ATP。目的1比较肿瘤部分消退(PR)率 用不同的无毒5元和6元ATP耗竭联合治疗来确定治疗效果 最好的对抗耐药乳腺癌异种移植。目的2评估肿瘤治疗后的nadir-ATP水平 活体被认为是与PR率相关性最好的原则证明。目标3评估的主要模式 治疗导致的细胞死亡。目的4评价远期疗效(治愈？)目标1：S最优 耐药异种移植物一年内的细胞杀伤诱导治疗作为指导 临床试验。临床上应以较少的毒副作用获得更好的疗效。 效果，因为抗癌药物的使用量是通常临床剂量的一半。如果在临床上得到验证， 提出的治疗方法将为转移性乳腺癌的治愈开辟道路，治疗策略可能会 将适用于其他耐药类型的癌症。

Chemotherapeutic cure of metastatic breast cancer is prevented by the inablility 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.