journal contribution
posted on 2023-03-31, 00:08 authored by Yuval Shaked, Elizabeth Pham, Santosh Hariharan, Ksenia Magidey, Ofrat Beyar-Katz, Ping Xu, Shan Man, Florence T.H. Wu, Valeria Miller, David Andrews, Robert S. Kerbel Levels of viable CEPs in the blood of Balb/c mice treated with escalating doses of capecitabine (S1); A flow chart of the image analysis (S2); Colonization of bone marrow derived cells in tumors from mice treated with LDM or MTD capecitabine regimens with or without LDM CTX assessed by flow cytometry (S3); Apoptosis and necrosis in tumors from mice treated with LDM or MTD capecitabine regimens with or without LDM CTX (S4); Microvessel density in tumors from mice treated with LDM or MTD capecitabine regimens with or without LDM CTX (S5); Liver metastasis in HT-29 bearing mice treated with MTD or LDM capecitabine regimens with or without LDM CTX (S6).
Funding
Israel Cancer Research Fund
European Research Council
Canadian Institutes of Health Research
Canadian Breast Cancer Foundation
CIHR
NSERC
CIHR Post-Doctoral Fellowship Award
History
ARTICLE ABSTRACT
Conventional chemotherapy drugs administered at a maximum tolerated dose (MTD) remains the backbone for treating most cancers. Low-dose metronomic (LDM) chemotherapy, which utilizes lower, less toxic, doses given on a close regular basis over prolonged periods, is an alternative and better tolerated potential strategy to improve chemotherapy. LDM chemotherapy has been evaluated preclinically and clinically and has shown therapeutic benefit, in both early and advanced stage metastatic disease, especially when used as a maintenance therapy. However, knowledge about the antitumor mechanisms by which LDM chemotherapy acts remain limited. Here we characterized the effects of LDM and MTD capecitabine therapy on tumor and host cells using high-throughput systems approaches involving mass spectrometry flow cytometry and automated cell imaging followed by in vivo analyses of such therapies. An increase in myeloid and T regulatory cells and a decrease in NK and T cytotoxic cells were found in MTD–capecitabine–treated tumors compared with LDM-capecitbine-treated tumors. Plasma from MTD capecitabine-treated mice induced a more tumorigenic and metastatic profile in both breast and colon carcinoma cells than plasma from mice treated with LDM capecitabine. These results correlated, in part, with in vivo studies using models of human or mouse advanced metastatic disease, where the therapeutic advantage of MTD capecitabine was limited despite a substantial initial antitumor activity found in the primary tumor setting. Overall these results implicate a possible contribution of immunologic host effects in accounting for the therapeutic limitations of MTD compared with LDM capecitabine. Cancer Res; 76(20); 5983–93. ©2016 AACR.
