This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Topotecan, a topoisomerase I inhibitor, is a drug made by Glaxo Smith Kline and sold as Hycamtin for treatment of patients with metastatic carcinoma of the ovary and small cell lung cancer (SCLC) after failure of initial or subsequent chemotherapy. Our long term goals are to optimize the dosing strategy of topotecan to achieve maximal efficacy and to identify, at the earliest time point possible, whether or not a particular patient will likely benefit from topotecan treatment. PET scan is proposed for this purpose. This study is intended to firstly demonstrate proof-of-principle that tumor uptake of topotecan can be measured in humans noninvasively with PET and secondly to provide evidence that PET-measured uptake has potential to be an early predictor of response to therapy. Topotecan blocks cell proliferation by blocking DNA replication. We intend to label topotecan with 11-C to create [11-C]topotecan, and to image its in vivo distribution in humans. Notably, this is the same molecule as the topotecan drug--the only difference is that an 11-C atom replaces a non-radioactive C atom. The objectives of this study are to: 1) label topotecan with 11-C 2) determine whether or not tumor uptake of [11-C]topotecan occurs quickly enough and at sufficient concentration to be measured immediately following a bolus of a tracer quantity 3) obtain preliminary indication of whether or not [11-C]topotecan imaging has potential to be an early predictor of response to topotecan therapy. A method to directly and noninvasively assess delivery of drug to tumors in humans has numerous applications. The potential of PET to determine quantitatively the levels of accumulation of chemotherapeutic agents in tumor offers the prospect of patient-specific dosing. We expect that PET-measured uptake of topotecan will be an early predictor of response to this therapy. It is already known that response rate is greater in patients with higher plasma levels of topotecan in lactone form. It may be that plasma levels serve as a surrogate to tumor drug accumulation and that direct measurement of drug concentration in tumor would be a better predictor of response than concentration in plasma. Subjects must have histologically documented ovarian carcinoma, small cell lung cancer, or other cancer with brain metastases that make the subject a candidate for topotecan therapy based on their primary oncologist's clinical decision. 10 subjects will be enrolled.
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