Tumors That Acquire Resistance to Low-Dose Metronomic Cyclophosphamide Retain Sensitivity to Maximum Tolerated Dose Cyclophosphamide

Abstract

Low-dose metronomic (LDM) chemotherapy is emerging as an alternative or supplemental dosing strategy to conventional maximum tolerated dose (MTD) chemotherapy. It is characterized primarily, but not exclusively, by antiangiogenic mechanisms of action and the absence of high-grade adverse effects commonly seen with MTD chemotherapy. However, similar to other anticancer therapies, inherent resistance to LDM chemotherapy is common. Moreover, even tumors that initially respond to metronomic regimens eventually develop resistance through mechanisms that are as yet unknown. Thus, we have developed in vivo models of PC-3 human prostate cancer cells resistant to extended LDM cyclophosphamide therapy. Such PC-3 variants show stable resistance to LDM cyclophosphamide in vivo yet retain in vitro sensitivity to 4-hydroperoxy-cyclophosphamide (precursor of the active cyclophosphamide metabolite 4-hydroxy-cyclophosphamide) and other chemotherapeutic agents, namely, docetaxel and doxorubicin. Moreover, LDM cyclophosphamide-resistant PC-3 variants remain sensitive to MTD cyclophosphamide therapy in vivo. Conversely, PC-3 variants made resistant in vivo to MTD cyclophosphamide show varying levels of resistance to metronomic cyclophosphamide when grown in mice. These results and additional studies of variants of the breast cancer cell line MDA-MB-231 suggest that resistance to LDM cyclophosphamide is a distinct phenomenon from resistance to MTD cyclophosphamide and that LDM cyclophosphamide administration does not select for MTD chemotherapy resistance. As such, our findings have various implications for the clinical use of metronomic chemotherapy.

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

“…Similar results were also found by Klement et al [7]. Nevertheless, in a pre-clinical study, it was demonstrated resistance to MCT, although due to different mechanisms than those involved in resistance to drugs administered in the maximum tolerated dose (MTD) [8].…”

Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model

“…Resistance to metronomic CPA has been associated with dormant stem-cell foci in hepatocellular carcinoma [51], ischemia-dependent K-ras mutations in colorectal carcinoma [52] and increased annexin A3 expression in prostate cancer [53; 54]. Different resistance mechanisms may be activated in different tumor models and by different CPA doses and schedules [55; 56]; these mechanisms could include immune-based resistance, as well as repopulation of quiescent tumor cells that are distal of blood vessel and deprived of oxygen and nutrients, selection of tumor cell populations with increased drug efflux and detoxification ability, increased DNA damage repair between metronomic CPA treatments, metabolic adaptation, and emergence of resistance to apoptosis [57; 58]. In preliminary studies of regressing GL261 tumors, we have seen ~2-fold higher expression of ALDH1A1 six days after two CPA injections on the CPA/9d compared to the CPA/6d schedule (unpublished results); ALDH1A1 inactivates CPA-derived aldophosphamide and can confer CPA resistance [59].…”

First-line metronomic chemotherapy in a metastatic model of spontaneous canine tumours: a pilot study

“…In this view, the use of CXB may have contributed both to a significant reduction of chemotherapy toxicity, such as haematological ones [33], and to the control of pain related to the disease. Moreover, a recent article by Emmenegger and colleagues [34] suggests that resistance to metronomic cyclophosphamide is a distinct phenomenon from resistance to maximum tolerated dose (MTD) cyclophosphamide and that metronomic cyclophosphamide administration does not select for MTD chemotherapy resistance. These findings, together with our data, may suggest to start metronomic cyclophosphamide earlier than previously thought, especially in a subset group such as frail and elderly patients, because of the open possibility to further treat these patients with MTD cyclophosphamide schedules without harming a possible response.…”