Evidence Implicating Immunological Host Effects in the Efficacy of Metronomic Low-Dose Chemotherapy

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.

Oral tegafur-uracil as metronomic therapy following intravenous FOLFOX for stage III colon cancer

“…Thus, the patients with metronomic UFUR might have lower disease burden when cancer relapse. This is compatible with the finding reported Shaked et al[18] They found oral daily metronomic chemotherapy, using cyclophosphamide and UFT, had high anti-metastatic effect. They also found that low dose metronomic chemotherapy, compared with maximum tolerated dose, had better therapeutic advantage on advanced metastatic disease.…”

Proinflammatory Macrophages Promote Multiple Myeloma Resistance to Bortezomib Therapy

“…Balb/c mice were treated with bortezomib or vehicle control, and after 24 hours, BM cells were flushed from femurs and tibia. The cells were immunostained with a mixture of metal-tagged antibodies (listed in Supplementary Table S2), and were used as previously described (17). The analysis of data were performed using Cytobank database (with viSNE algorithm), as previously described (18), when gating on CD45 þ cells.…”

Resistance to metronomic chemotherapy and ways to overcome it

“…The VEGF (-634CC) genotype was significantly associated with a shorter progression free survival. Genetic heterogeneity may not only affect the antivascular but also the immunomodulatory activities of MC [60]. …”