Low-dose Metronomic Combined with Intermittent Bolus-dose Cyclophosphamide Is an Effective Long-term Chemotherapy Treatment Strategy

Abstract

Metronomic chemotherapy refers to the close, regular administration of comparatively low doses of cytotoxic drugs, with minimal or no drug-free breaks, over prolonged periods. It is thought to have an antiangiogenic basis. However, whereas surprisingly durable and potent tumor responses have been observed in a number of preclinical tumor models, relapses usually eventually occur using this type of treatment strategy. We therefore decided to test modified metronomic chemotherapy regimens that might significantly delay such relapses, but still maintain modest and acceptable toxicity profiles. Here, we show that repeated administration of bolus doses (BDs) of cyclophosphamide every 3 or 6 weeks, combined with a daily oral low-dose metronomic (LDM) regimen (20 mg/kg/d cyclophosphamide), improves efficacy and significantly delays progression of transplanted PC-3 human prostate cancer xenografts, syngeneic transplanted EMT-6 breast tumors, and ''spontaneous'' murine erythroleukemia. Efficacy was superior whereas toxicity was mild and comparable to the LDM regimen, the latter assessed by body weight, neutrophil, lymphocyte, and total white blood counts. Antiangiogenic activity, measured by reduction in circulating endothelial precursor cells, revealed that the greatest degree of suppression occurred using the combination treatment. Overall, our results indicate that the administration of intermittent BD combined with chronic oral LDM cyclophosphamide is a potent treatment regimen for controlling tumor growth, which has a low toxicity profile, over prolonged periods of time. (Cancer Res 2005; 65(16): 7045-51)

Long-term progression and therapeutic response of visceral metastatic disease non-invasively monitored in mouse urine using β-human choriogonadotropin secreting tumor cell lines

“…Metronomic administration (20 mg/kg/d) of cyclophosphamide was carried out by addition of the drug to the drinking water as originally described (10), and later modified (14) by the addition of an upfront i.p. bolus dose (150 mg/kg).…”

“…These were treated with control PBS i.p., or administered a bolus plus oral low-dose metronomic cyclophosphamide regimen (as described in ref. 14), or given DC101 i.p. (15).…”

Role of endothelial progenitor cells in breast cancer angiogenesis: from fundamental research to clinical ramifications

“…Metronomic chemotherapy is defined as regular administration of a chemotherapeutic drug at relatively low (nontoxic) doses, over prolonged periods, with no extended drug-free break periods [63]. Using different preclinical breast cancer models, several studies showed a strong relationship between decreased number of circulating EPC and efficiency of various metronomic chemotherapy regimens [65][66][67][68]. These studies demonstrated that EPC can be used successfully as a surrogate marker in mice for determining the optimal biological dose for various metronomic chemotherapies, thus avoiding empiricism (at least in mice), with respect to determining the optimal biological dose in metronomic chemotherapy regimens.…”

Metronomic chemotherapy following the maximum tolerated dose is an effective anti‐tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells

“…MTD chemotherapy would debulk the tumour before the initiation of MET, which would then have an anti-angiogenic effect, while abolishing the endothelial cell rebound. 6 The concepts of combining MET with MTD chemotherapy or with agents targeting vascular endothelial growth factor …”

“…MTD chemotherapy would debulk the tumour before the initiation of MET, which would then have an anti-angiogenic effect, while abolishing the endothelial cell rebound. 6 The concepts of combining MET with MTD chemotherapy or with agents targeting vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors were brought together in a single pre-clinical study reported by Pietras and Hanahan. 7 In this article, we generalise this chemo-switch (C-S) concept to other tumour models and other drugs, evaluating its effects on angiogenesis and cancer stem cell (CSC) number.…”