Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin.
Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin.
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DOI：
10.1002/nbm.3240
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发表时间：
2015-03
影响因子：
2.9
通讯作者：
Glickson, Jerry D.
中科院分区：
文献类型：
--
作者：
Nath, Kavindra;Nelson, David S.;Heitjan, Daniel F.;Leeper, Dennis B.;Zhou, Rong;Glickson, Jerry D.
关键词：
我们证明了氯硝胺(LND，100 mg/kg，i.p.)的作用。在许多人类癌症的异种移植模型中，包括DB-1黑色素瘤和HCC1806乳腺癌、BT-474乳腺、LNCaP前列腺癌和A2870卵巢癌，都是相似的。在LND治疗后，这些肿瘤在2-3小时内都表现出细胞内pH的迅速下降，细胞外pH的小幅下降，伴随的核苷三磷酸的单调下降和无机磷的增加。我们先前证明，选择性细胞内酸化增强了黑色素瘤模型对马法兰(7·5 mg/kg)的反应，根据肿瘤生长延迟分析，估计产生%的细胞杀伤率。我们现在证明，在DB-1黑色素瘤和HCC1806乳腺癌中，LND在7.5 mg/kg静脉注射时增强了对DB-1黑色素瘤中产生95%细胞杀伤率的阿霉素的反应。阿霉素和98%的细胞杀伤率分别为10.0 mg/kg和12.0 mg/kg，对HCC1806乳腺癌的细胞杀伤率为95%。阿霉素的增敏作用可能是由于弱碱性的蒽环类药物的阳离子捕获所致。最近临床治疗黑色素瘤和其他形式的人类癌症的经验表明，除了手术外，这些疾病可能无法通过单一的治疗程序治愈。将需要一个多模式的治疗方法。作为一种有效的调节肿瘤对N-芥子和蒽环类药物的反应以及对肿瘤的热敏感性和放射敏感性的调节因子，LND有望在治疗和可能完全控制多种流行的人类癌症方面发挥重要的临床作用。
We demonstrate that the effects of lonidamine (LND, 100 mg/kg, i.p.) are similar for a number of xenograft models of human cancer including DB-1 melanoma and HCC1806 breast, BT-474 breast, LNCaP prostate and A2870 ovarian carcinomas. Following treatment with LND, each of these tumors exhibits a rapid decrease in intracellular pH, a small decrease in extracellular pH, a concomitant monotonic decrease in nucleoside triphosphate and increase in inorganic phosphate over a 2–3 hr period. We previously demonstrated that selective intracellular tumor acidification potentiates response of this melanoma model to melphalan (7.5 mg/kg, i.v.), producing an estimated 89% cell kill based on tumor growth delay analysis. We now show that in both DB-1 melanoma and HCC1806 breast carcinoma, LND potentiates response to doxorubicin producing 95% cell kill in DB-1 melanoma at 7.5 mg/kg, i.v. doxorubicin and 98% cell kill at 10.0 mg/kg doxorubicin, and in HCC1806 breast carcinoma producing a 95% cell kill at 12.0 mg/kg doxorubicin. Potentiation of doxorubicin can result from cation trapping of the weakly basic anthracycline. Recent experience with the clinical treatment of melanoma and other forms of human cancer suggests that these diseases will probably not be cured by a single therapeutic procedure other than surgery. A multimodality therapeutic approach will be required. As a potent modulator of tumor response to N-mustards and anthracyclines as well as tumor thermo- and radiosensitivity, LND promises to play an important clinical role in the management and possible complete local control of a number of prevalent forms of human cancer.
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影响因子：
3.1
作者：
Bezabeh, T;Evelhoch, JL;Ackerman, JJH
通讯作者：
Ackerman, JJH
影响因子：
3.5
作者：
PACILIO, G;CARTENI, G;DECESARE, M
通讯作者：
DECESARE, M
影响因子：
2.9
作者：
Nath, Kavindra;Nelson, David S.;Ho, Andrew M.;Lee, Seung-Cheol;Darpolor, Moses M.;Pickup, Stephen;Zhou, Rong;Heitjan, Daniel F.;Leeper, Dennis B.;Glickson, Jerry D.
通讯作者：
Glickson, Jerry D.
影响因子：
3.9
作者：
Ben-Yoseph, O;Lyons, JC;Ross, BD
通讯作者：
Ross, BD
影响因子：
--
作者：
Montanari, Marco;Fabbri, Francesco;Cruciani, Giorgio
通讯作者：
Cruciani, Giorgio