Low-dose metronomic delivery of cyclophosphamide is less detrimental to granulosa cell viability, ovarian function, and fertility than maximum tolerated dose delivery in the mouse†

Abstract

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 was 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.

Ameliorative effect of recombinant human lactoferrin on the premature ovarian failure in rats after cyclophosphamide treatments

“…And the results showed that the rhLF treatments significantly protected the primary rat GCs from the 4-HC treatments via the inhibition of ROS production and the promotion of cellular proliferation, which was consistent with the in vivo results of rhLF administrations. In addition, the high expression levels of Bax after 4-HC treatments revealed the increased levels of cellular apoptosis, which was consistent with these previous studies about the exposure to chemotherapy drugs in vitro and high levels of GCs apoptosis [5,14,55,82], and our results further confirmed the main target of rhLF treatments during POF was GCs. However, due to the complex in vivo microenvironments including oocytes and follicular cells (GCs, theca cells and stroma cells) in mammalian ovaries, the ameliorative target of rhLF on the POF damages needs more detailed in vitro investigations.…”

Parthenolide enhances the metronomic chemotherapy effect of cyclophosphamide in lung cancer by inhibiting the NF-kB signaling pathway

“…In a study conducted by Dynes et al [ 36 ], it was demonstrated that metronomic chemotherapy using a dosage of 20 mg/kg/day CTX in mice was effective. Therefore, for this study, metronomic chemotherapy was administered to mice with a CTX dose of 20 mg/kg/day.…”

The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency

“…To evaluate the effect of Cy on activation of cellular senescence, GLCs were treated with an active metabolite of Cy, 4-HC [32,33] (Toronto Research Chemicals, Toronto, ON, Canada), at concentrations of 0.001-100 µM for 24 h. These conditions were chosen based on previous studies that used human cells or animal GLCs [34][35][36]. Treatment with 10 µM 4-HC for 24 h exerted the maximum effect without changing cellular morphology.…”