Metronomics Global Health Initiative

Home page > Publications > Papers of Interest > Metronomic in adult > Metronomic delivery of cyclophosphamide

Metronomic delivery of cyclophosphamide is less detrimental to granulosa cell viability, ovarian function, and fertility than MTD

Dynes J, Osz K, Hooper A and Petrik J. from the Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada. have just published an article entitled Low Dose Metronomic Delivery of Cyclophosphamide is Less Detrimental to Granulosa Cell Viability and Ovarian Function Than Maximum Tolerated Dose Delivery in the Mouse in Biology of Reproduction. In this article they show using mice model that metronomic cyclophosphamide induces less follicule atresia than MTD cyclophosphamide suggesting it might minimize tlong term effect of alkylating agents on fertility.


Chemotherapy can cause early menopause or infertility in women and have a profound negative impact on the quality of life of young female cancer survivors. Various factors are known to influence the risk of chemotherapy-induced ovarian failure, including the drug dose and treatment duration; however, the scheduling of dose administration has not yet been evaluated as an independent risk factor. We hypothesized that Low-Dose Metronomic (LDM) chemotherapy scheduling would be less detrimental to ovarian function than the traditional Maximum-Tolerated Dose (MTD) strategy. In vitro, MTD cyclophosphamide exposure resulted in decreased proliferation and increased granulosa cell apoptosis, while cells treated with LDM cyclophosphamide were not different from untreated controls. Treatments of MTD cyclophosphamide induced high levels of follicle atresia and enhanced follicle recruitment in mice. In contrast, LDM delivery of an equivalent dose of cyclophosphamide reduced growing follicle numbers, but was not associated with higher levels of follicle atresia or recruitment. MTD cyclophosphamide induced significant vascular disruption and DNA damage in vivo, while LDM chemotherapy with equal cumulative amounts of cyclophosphamide were not different from controls. MTD chemotherapy also had a negative effect on mouse fertility outcomes. Our findings suggest that LDM scheduling could potentially minimize the long-term effects of cyclophosphamide on female fertility by preventing follicle depletion from enhanced activation.

You can access full text here.