Enhanced RF Tumor Ablation with Liposomal Chemotherapy

脂质体化疗增强射频肿瘤消融

• 批准号: 6929231
• 负责人: S. NAHUM GOLDBERG
• 金额: $ 41.15万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929231
• 关键词: antineoplastics; combination cancer therapy; cytotoxicity; dogs; doxorubicin; liposomes; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplasm /cancer thermotherapy; neoplastic process; oxidative stress; radiation dosage; radiowave radiation; sarcoma

DESCRIPTION (provided by applicant): Image-guided radiofrequency (RF) tumor ablation is being used to treat focal liver, renal, and other tumors. Yet, complete ablation is often difficult to achieve, particularly at tumor margins, presenting substantial barriers toward clinical efficacy. Our preliminary studies take advantage of complementary interactions between RF ablation and liposomal doxorubicin, and demonstrate that this combination may markedly increases tumor destruction in animals and patients, and animal survival compared to RF alone or RF combined with free doxorubicin. RF ablation also increased intratumoral liposomal doxorubicin 7 fold compared to controls, particularly in a peripheral region immediately adjacent to the zone of RF induced coagulation. Thus, this combined treatment paradigm has the unique potential both to potentiate preferential delivery of cytotoxic agents in liposomal vehicles, and to maximize the completeness of ablation of a treated tumor, in humans. Our immediate goals are to address several key issues that require further knowledge prior to initiation of Phase II or larger multicenter clinical trials. 1) Our data indicate that gains in both drug uptake and tumor destruction can be further increased through the systematic optimization of the relevant treatment parameters. 2) The mechanisms driving this interaction particularly the hyperthermic dosimetry of increased tissue destruction and the causes for increased tumor destruction seen when empty liposomes are given without doxorubicin need to be better understood, as this could lead to developing clinical strategies having even greater efficacy. 3) Local and systemic toxicities need to be better defined. This will be accomplished over 3 aims. 1) We will improve tumor destruction of combined therapy using simplex optimization in canine venereal sarcoma. The relationship between intratumoral thermal dosimetry to increased doxorubicin uptake and increased tumor destruction will be characterized to elucidate the role of hyperthermia, threshold thermal dosage, and the conditions under which combined therapy is most effective. 2) We will test specific hypotheses about the possible role of the liposome carrier components. RF and empty liposomes will be studied to define the relative contributions of the lipids and of the doxorubicin to the mechanisms of cell killing. We will further determine whether increased tumor destruction can be ascribed to enhanced oxidative stress and lipid peroxidation and whether manipulation of the substrate upon which lipid peroxidation occurs can further potentiate the antitumor effect of thermal ablation. 3) We will characterize potential local and systemic treatment toxicity including determining the thermal dosimetry at which tissue effects are seen in normal canine liver and kidney and in a one-month survival study in renal tumors.

描述（由申请人提供）：图像引导射频（RF）肿瘤消融术用于治疗局灶性肝、肾和其他肿瘤。 然而，完全消融通常难以实现，特别是在肿瘤边缘，从而对临床疗效造成实质性障碍。 我们的初步研究利用RF消融和脂质体阿霉素之间的互补相互作用，并证明这种组合可以显着增加动物和患者的肿瘤破坏，以及与单独RF或RF与游离阿霉素组合相比的动物存活率。 与对照组相比，射频消融也使瘤内脂质体阿霉素增加了7倍，特别是在紧邻射频诱导凝固区的外周区域。 因此，这种组合治疗模式具有独特的潜力，既可以增强脂质体载体中细胞毒性剂的优先递送，又可以最大限度地提高人类治疗肿瘤的消融完整性。 我们的近期目标是解决几个关键问题，需要进一步的知识之前，启动II期或更大的多中心临床试验。 1)我们的数据表明，通过系统优化相关治疗参数，可以进一步增加药物摄取和肿瘤破坏的收益。 2)需要更好地理解驱动这种相互作用的机制，特别是组织破坏增加的高热剂量测定法和当给予空脂质体而不给予阿霉素时观察到的肿瘤破坏增加的原因，因为这可能导致开发具有更大功效的临床策略。 3)需要更好地定义局部和全身毒性。 这将通过三个目标来实现。 1)我们将利用单纯形优化法来提高犬性病肉瘤综合治疗的肿瘤破坏率。 肿瘤内热剂量测定增加阿霉素摄取和增加肿瘤破坏之间的关系将被表征，以阐明高温的作用，阈值热剂量，以及联合治疗最有效的条件。 2)我们将检验关于脂质体载体组分可能作用的具体假设。 将研究RF和空脂质体，以确定脂质和多柔比星对细胞杀伤机制的相对贡献。 我们将进一步确定是否增加肿瘤破坏可以归因于增强的氧化应激和脂质过氧化，以及是否操纵的基板上发生脂质过氧化可以进一步增强热消融的抗肿瘤作用。 3)我们将表征潜在的局部和全身治疗毒性，包括确定在正常犬肝脏和肾脏中以及在肾肿瘤的一个月生存研究中观察到组织效应的热剂量测定法。