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.
Highlights
Conventional chemotherapy is commonly administered at maximum tolerated doses (MTD)
The SPADE analysis of bone marrow–derived cell (BMDC)-colonizing tumors from all treated groups revealed a significant enrichment of myeloid-derived suppressor cell (MDSC) subpopulations in MTD capecitabine group (13/23 clusters), whereas in Low-dose metronomic (LDM) capecitabine and/or control groups there was a significant enrichment in macrophages and monocytic cell subpopulations (16/21 clusters) and NK-cell subpopulations (2/2 clusters; Fig. 1A)
The changes found in the percentage of MDSCs, NK cells, and macrophages were validated by flow cytometry (Supplementary Fig. S3A)
Summary
Conventional chemotherapy is commonly administered at maximum tolerated doses (MTD). This usually requires extended breaks (e.g., 2–3 weeks) to allow recovery from associated toxic side effects. Endothelial progenitor cells, and various myeloid cells or macrophages were shown to home to the tumor site and induce tumor angiogenesis following therapy [5,6,7] This reactive BMDC host response is accompanied by a systemic induction of various cytokine and growth factors, which contribute to tumor regrowth and to metastasis [8, 9]. Normal mice "preconditioned" by paclitaxel and subsequently given an intravenous injection of Lewis lung carcinoma cells succumb to pulmonary metastasis earlier than control mice [9] These results further suggest that reactive host responses following MTD chemotherapy can potentially generate tumor growth–promoting prometastatic effects, negating or even completely blunting the desired antitumor cell activity of the drug used
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