A phase 0 pilot study to determine if papaverine increases oxygenation in spontaneous canine soft tissue sarcoma

摘要 肿瘤缺氧通过减少递送到肿瘤的有效剂量而降低放射治疗的有效性。 严重缺氧的细胞需要2.8倍的剂量才能达到与完全缺氧的细胞相同的细胞杀伤效果。 充氧出于这个原因，许多研究小组试图向肿瘤输送更多的氧气，作为一种治疗方法， 缺氧和增加放射敏感性。这些策略确实有效地使啮齿动物中的模型肿瘤放射增敏， 但在人体试验中并不成功。我们已经从不同的生物学角度看待肿瘤氧合， 成功观和评价观。从生物学角度来说，如果我们能在临床上减少氧气 不增加其供应，而增加其需求，我们可以有效地减少缺氧和产生肿瘤 放射增敏。我们已经确定罂粟碱是FDA批准的分子， 临床剂量下的线粒体功能。对小鼠肿瘤的研究支持罂粟碱可以 通过调节氧消耗，产生“代谢性放射增敏”。方面 罂粟碱的评价，我们建议测试其作为一种临床放射增敏剂在异质 在俄勒冈州立大学兽医学院接受治疗的自发性犬软组织肉瘤的人群。的 异质性宿主和肿瘤遗传学产生了一个临床试验，我们假设它将更具有预测性 人类的成功比啮齿类动物的研究。罂粟碱不是针对特定的癌症突变， 在存在缺氧的任何实体瘤中作为放射增敏剂有效。拟议的研究将是0期 药效学研究，将确定罂粟碱是否可以增加犬软组织的氧合 通过近红外光谱（FD-NIRS）技术真实的实时测量肉瘤。我们建议测试10 1 mg/kg组10只，2 mg/kg组10只。相关的生物学研究将确定， 基线肿瘤缺氧或其它生物学变量可以预测对罂粟碱的反应。这些研究将 确定犬软组织肉瘤是否是一个可行的系统来测试新的缺氧肿瘤放射增敏剂， 罂粟碱在未来的介入试验中应被视为潜在的放射增敏剂。

ABSTRACT Tumor hypoxia reduces the effectiveness of radiotherapy by reducing the effective dose delivered to the tumor. Cells that are severely hypoxic require 2.8-fold greater dose to achieve the same cell kill as those that are fully oxygenated. For this reason, many groups have tried to deliver more oxygen to tumors as a therapy to reduce hypoxia and increase radiosensitivity. These strategies did effectively radiosensitize model tumors in rodents, but did not prove successful in human trials. We have looked at tumor oxygenation differently from the biological perspective and the evaluation of success perspective. In terms of biology, if we could clinically reduce oxygen demand rather than increase its supply, we could effectively reduce hypoxia and produce tumor radiosensitization. We have identified papaverine as an FDA-approved molecule with the ability to inhibit mitochondrial function at clinical doses. Studies in mouse tumors support the idea that papaverine can radiosensitize through regulation of oxygen consumption, producing “Metabolic Radiosensitization”. In terms of the evaluation of papaverine, we propose to test its potential as a clinical radiosensitizer in a heterogeneous population of spontaneous canine soft tissue sarcomas being treated at OSU Veterinary Medical School. The heterogeneous host- and tumor genetics generate a clinical trial that we hypothesize will be much more predictive of human success than a rodent study. Papaverine is not targeted to a specific cancer mutation, and should be effective as a radiosensitizer in any solid tumor where hypoxia exists. The proposed study will be a phase 0 pharmacodynamics study that will determine if papaverine can increase oxygenation in canine soft tissue sarcoma as measured by near infrared spectroscopy (FD-NIRS) technology in real time. We propose to test 10 animals with 1 mg/kg and 10 animals with 2 mg/kg papaverine. Correlative biological studies will determine if baseline tumor hypoxia or other biological variables can predict response to papaverine. These studies will determine if canine soft tissue sarcoma is a feasible system to test new hypoxic tumor radiosensitizers, and if papaverine should be considered as a potential radiosensitizer in future interventional trials.