Systemic Chemotherapy of Melanoma: NMR Studies of Lonidamine & N-Mustard Activity

黑色素瘤的全身化疗：洛尼达明的 NMR 研究

• 批准号: 8450752
• 负责人: JERRY D GLICKSON
• 金额: $ 43.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-21 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450752
• 关键词: Acids; Affect; Aftercare; Alkylating Agents; Bioenergetics; Blood; Body Weight decreased; Bone Marrow; Brain; Cancer Patient; Cardiac; Cell Respiration; Cell membrane; Chlorambucil; Choline; Clinic; Clinical; Clinical Trials; Complete Blood Count; Cyclophosphamide; DNA Repair; Detection; Diffusion; Disease; Dose; Drug Kinetics; Early Diagnosis; Electrocardiogram; Electrolytes; Exhibits; Funding; Future; Glucose; Glutathione S-Transferase; Glycolysis; Goals; Growth; Heart; High Pressure Liquid Chromatography; Histopathology; Homeostasis; Human; Hyperglycemia; Imidazole; Individual; Infusion procedures; Injection of therapeutic agent; Ions; Lactic acid; Life; Liver; Lonidamine; Magnetic Resonance Imaging; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Melphalan; Metastatic Melanoma; Methods; Mitochondria; Modeling; Monitor; Monocarboxylic Acid Transporters; Mus; Mustard; Mustard Agent; Nitrogen; Normal Cell; Normal tissue morphology; Nude Mice; Organ; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiologic pulse; Preparation; Procedures; Propionic Acids; Protocols documentation; Pyruvate; Recovery; Regimen; Relative (related person); Renal function; Resolution; Respiration; Schedule; Serum; Skeletal Muscle; Skin Cancer; Staging; Stimulus; Systemic Therapy; Therapeutic; Therapeutic Index; Time; Toxic effect; Transferase; Tumor Volume; Ursidae Family; Virulent; Xenograft Model; Xenograft procedure; aminopropylphosphonate; base; cancer cell; cell killing; chemotherapy; extracellular; inhibitor/antagonist; liver function; meetings; melanoma; mortality; neoplastic cell; non-invasive monitor; pH gradient; pre-clinical; programs; research clinical testing; response; response marker; temozolomide; transport inhibitor; tumor

DESCRIPTION (provided by applicant): Melanoma remains one of the deadliest of human cancers with no effective method for treating the disseminated disease. We propose to develop an effective method for systemic chemotherapy of melanoma by [tumor] selective [intracellular] acidification to sensitize melanomas to N-mustard alkylating agents. Our strategy is to coadminister glucose with the monocarboxylic acid transport (MCT) inhibitor lonidamine LND in order to trap lactic acid produced by glycolysis in the tumor and to inhibit oxidative metabolism by impeding pyruvate trans- port into mitochondria. This approach depends on the MCT being the key pathway for tumor intracellular pH (pHi) homeostasis, which has been confirmed in our melanoma models. Previous treatment with LND under hyperglycemic conditions led to some mortality. We were funded on this 2yr R01 to develop a safe reproducible method for acidification of human DB1 melanoma xenografts with LND. By administering LND 100 mg/kg i.p. without glucose, we have achieved acidification of the tumor to a pHi of 6.4¿0.1 for at least hr during which time the NTP/Pi ratio of the tumor decreased by 50%; there was no mortality, no significant loss of weight and minimal toxicity associated with this treatment. [LND induced minimal changes in extracellular pH (pHe) of normal tissue, but modified the pH gradient across the plasma membrane of the tumor from pretreatment values of pHi 6.9, pHe 7.0 or !pH=~0 to a post-treatment values of pHi=6.4, pHe=6.85 or !pH=-0.45. Steady state lactate in the tumor increased 3-fold relative to pre-LND levels.] Respiration, EKG, electrolyte levels and blood oxygenation did not change, while blood analysis is still in progress. The pHi and ATP/Pi of skeletal muscle did not change, and there was only a small transient decrease in pHi and ATP/Pi of the liver. Melphalan (LPAM 7.5 mg/kg i.v.)+ LND exhibited a growth delay of 10.5¿0.5 d vs. LND alone, 0.6¿0.7 d. and LPAM alone 1.4¿0.1 d. The [enhanced] response of LPAM to acidification is attributed to an increase in the concentration of the active intermediate (aziridinium ion), a decrease in GSH due to decreased activity of glutathione-S-transferase and a decrease in DNA repair resulting from acid inhibition of O6-alkyl-transferase. Tumor volume decreased by 52.5 ¿12.5%, consistent with the estimated log10 cell kill=0.3012 = log10(2.0). These preliminary studies set the stage for implementation of multidose systemic treatment of xenograft models of human melanoma in preparation for eventual clinical trials. The Aims of this renewal proposal are: 1) To maximize tumor acidification while still avoiding life threatening toxicity by coadministration of low levels of glucose with LND, and to also extend these studies to the more glycolytic DB8 melanoma human xenograft model. 2) Since other N-mustard agents might exhibit similar enhancements of activity at acidic pHi values but perhaps with lower toxicity, LPAM will be compared with cyclophosphamide, chlorambucil and bendamustine under single and multidose administration. 3) To evaluate potential 1H NMR markers for noninvasive early detection of response--lactate and total choline by MRS and apparent diffusion constant (ADC) and T2 measured by MRI.

描述（由适用提供）：黑色素瘤仍然是最致命的人类癌症之一，没有治疗传播疾病的有效方法。我们建议通过[肿瘤]选择性[细胞内]酸化对黑色素瘤进行全身化疗的有效方法，以将黑色素瘤与N-粘液烷基化剂感知黑色素瘤。我们的策略是将葡萄糖与单羧酸转运（MCT）抑制剂lonidamine LND共同诱导糖酸乳酸在肿瘤中产生的乳酸，并通过将丙酮酸跨型型糖化剂抑制氧化代谢。这种方法取决于MCT是肿瘤内pH（PHI）稳态的关键途径，这在我们的黑色素瘤模型中已得到证实。在高血糖条件下使用LND治疗的先前治疗导致了一些死亡率。我们在这个2yR R01上资助了一种安全可重复的方法，用于使用LND酸化人DB1黑色素瘤。通过管理LND 100 mg/kg I.P.在没有葡萄糖的情况下，我们至少将肿瘤的PHI酸化至6.4€0.1，在此期间，肿瘤的NTP/PI比降低了50％。没有死亡率，没有显着的体重减轻和这种治疗方法相关的最小毒性。 [LND诱导正常组织的细胞外pH（PHE）的最小变化，但从PHI 6.9的预处理值，PHE 7.0或！pH = 〜0的预处理值中修饰了肿瘤跨质膜的pH梯度，以pHi = 6.4，pHe = 6.85 = 6.85或！pH = 6.85或！pH = -0.45。相对于LND前水平，肿瘤中的稳态乳酸增加了3倍。骨骼肌的PHI和ATP/PI没有变化，肝脏的PHI和ATP/PI只有很小的短暂性下降。 Melphalan（LPAM 7.5 mg/kg i.v。）+ LND暴露了10.5 d d vs. LND的生长延迟，0.6¿0.7d。单独使用LPAM1.4¿0.1d。 LPAM对酸化的[增强]响应归因于活性中间体（氮杂丁酮离子）的浓度升高，由于谷胱甘肽-S-转移酶的活性降低而导致GSH的降低以及DNA修复的降低，导致o6-烷基转移酶的酸抑制酸性抑制酸。肿瘤体积减少了52.5»12.5％，与估计的Log10细胞杀死= 0.3012 = log10（2.0）一致。这些初步研究为实施人黑色素瘤异种移植模型的多蛋白系统治疗奠定了基础，以准备最终的临床试验。该更新建议的目的是：1）最大化肿瘤酸化，同时仍然避免通过将低水平的葡萄糖与LND共同给药，并将这些研究扩展到更糖酵解的DB8黑色素瘤人类黑色素瘤模型。 2）由于其他N-Mustard剂可能在酸性PHI值下可能存在类似的活性增强，但可能具有较低的毒性，因此将LPAM与环磷酰胺，chlorambucil和Bendamustine进行比较，在单一和多剂量给药下。 3）评估潜在的1H NMR标记物通过MRS对反应 - 乳酸和总胆碱的无创早期检测，并通过MRI测量的明显扩散常数（ADC）和T2。