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    Awarded Grants
    Enhancement of Radiotherapy of Breast Cancer by a Novel Chemoradiosensitizing Agent

    Scientific Abstract:
    A novel radiosensitizing agent, camp-metro, where a metrophenoxyacetic acid is attached at the C20(S) position of lactone ring has been synthesized and found to be significantly more effective in killing human breast cancer cells than topotecan. The sensitizer enhancement ratio of camp-metro was 1.4 for treatment of breast cancer cells. Mice bearing MTG-B mouse mammary tumors treated with camp-metro and 8 Gy radiation exhibited 100% tumor-free, but none with topotecan and radiation. Equally important, the toxicity of camp-metro was 18.7 times lower than that of topotecan. The hypotheses are advanced: (1) camp-metro with radiosensitizing and stabilizing groups at the C20(S) position of lactone ring may be superior to topotecan for chemoradiosensitization of breast cancers (increased efficacy and reduced drug toxicity) in vivo; (2) mechanisms for striking chemoradiosensitizing effects of camp-metro on breast cancers may include the increased apoptosis via activation of its molecular pathways, the increased DNA damage and the inhibition of DNA repair. Specific aims in this proposal are: 1) to test chemotherapeutic and radiosensitizing effects of camp-metro in nude mice bearing two human breast cancer xenografts (MDA-MB-231 and MDA-MB-453) by the tumor regrowth assay; 2) to investigate drug pharmacokinetics of camp-metro in both normal and breast cancer xenograft bearing athymic mice by HPLC analysis; 3) to study cytotoxic and radiosensitizing effects of camp-metro in normal tissues (intestine, bone marrow) by crypt survival and spleen colony assays; 4) to elucidate the cellular and molecular mechanisms that might account for remarkable action of camp-metro in chemoradiosensitizing human breast cancer cells using a variety of methods. These specific aims are designed to answer the questions how this novel camptothecin analog chemoradiosensitizes human breast cancers, how it proves to be significantly more effective in killing breast cancer cells than topotecan, and why its toxic side effects is dramatically less than that of topotecan. If therapeutic effects similar to those noted in tissue culture and in mice could be achieved on human breast cancers, the clinical benefits to breast cancer patients would be substantial.

    Lay Abstract:
    LAY ABSTRACT: Topotecan is a new anticancer drug developed in 1990s. However, toxic side effects, such as neutropenia and thrombocytopenia, have limited the usefulness of this drug. We are seeking to develop and test a novel second-generation version of topotecan that is more effective in killing human breast cancer cells as a radiation enhancement agent, but less toxic to normal tissues. Our preliminary results indicate that this second-generation analog of topotecan is substantially more effective against breast cancer cells than topotecan. It also has 100% curative effects on mouse mammary tumors in mice, but none with topotecan. Moreover, this analog is significantly less toxic to normal mice than topotecan. The key active structure of this analog is highly stable in human plasma, but not that of topotecan. We plan to test this promising analog on two human breast cancers grown in nude mice, and to evaluate its therapeutic efficacy at clinically relevant doses for future application in human breast cancer therapy. In these studies its drug effects will be evaluated alone and in combination with radiotherapy, compared to those of topotecan. These preclinical studies of this nature are complex and laborious, but they provide essential information on therapeutic properties of topotecan analog under clinically relevant conditions. Based on preliminary results it is hoped that these novel topotecan analog will be superior to topotecan, providing a unique combination of improved therapeutic action in killing breast cancer cells without any penalty in the form of increased drug toxicity. The development of newly synthesized second-generation topotecan analog with higher efficacy and reduced toxicity holds a considerable promise for dramatically improved therapy of breast cancers. The proposed studies in this project will directly contribute to the design of clinical trials and to the development of this novel topotecan analog as a clinically useful therapeutic agent for conquering breast cancers. If therapeutic effects similar to those noted in tissue culture and in mice could be obtained in clinical trials, the benefits to breast cancer patients would certainly be enormous.