Efficacy and Safety of Systemic and Locoregional Cisplatin Chronotherapy in Rats with Ovarian Carcinoma

Abstract

Aim: Alterations in circadian rhythms caused by tumor growth are thought to be clinically relevant as they affect the prognosis and treatment response. We aimed to evaluate the chronotherapeutic approach in rats with ovarian cancer receiving cisplatin intravenously (IV) or with hyperthermic intraperitoneal chemoperfusion (HIPEC) and to assess daily variations in tumor and intestinal epithelium proliferation. Methods: In the pilot study, we used 12 intact rats and 12 rats with transplantable ovarian cancer, which were euthanized at ZT0 (08:00, lights on), ZT6, ZT12 and ZT18. In the main study, we used 45 rats with transplantable ovarian cancer. Animals were randomized into five groups: control, HIPEC with cisplatin at ZT0 (08:00), HIPEC with cisplatin at ZT12 (20:00), IV cisplatin at ZT0 and IV cisplatin at ZT12. We assessed the proliferation rate of tumor and small intestinal epithelium, apoptosis in small intestinal epithelium, and levels of γ-H2AX (DNA damage/repair marker) in kidneys and liver. Survival was calculated in each group. Results: Ascitic ovarian cancer disrupted daily variations in intestinal epithelium proliferation and DNA damage/repair in rats. Ovarian carcinoma exhibited no daily variation in mitotic activity. In animals receiving IV cisplatin, massive cell damage in the renal medulla and cystic changes within renal tubules were observed, unlike in rats receiving HIPEC. Tumor mitotic activity was lower in morning-treated groups. The median survival of rats in the control group was 8.5 days (95% CI 6.0-22.0), in HIPEC at ZT0 40.5 days (95% CI 28.0-47.0, p<0.001) and in HIPEC at ZT12 32.0 days (95% CI 28.0-37.0, p<0.001). Conclusion:In a rat model, ovarian tumor growth disrupted daily variations in intestinal epithelium proliferation and caused genotoxic stress in tumor-free tissues. HIPEC with cisplatin at ZT0 had a better efficacy/toxicity profile than HIPEC with cisplatin at ZT12 and IV administration at both time points.

Gender and Sex-Related Differences in Normal Tissue Effects Induced by Platinum Compounds

“…The evidence-based fact that certain chemotherapeutic agents induce fewer side effects when administered at night while others are more efficient on tumour cells when given daytime, should be sufficiently convincing to take the necessary steps to regard chronotherapy as the fourth dimension of oncological treatment [64]. For instance, a recent study on the efficacy and safety of cisplatin chronotherapy in rats with ovarian carcinoma reported less toxicity with the morning administration of the drug as compared to evening chemotherapy, including nephrotoxicity, liver toxicity and gastrointestinal toxicity [65]. This observation confirms the results of other chronotherapy studies on the platinum toxicity profile, where morning cisplatin led to less severe peripheral neuropathy as compared to evening treatment [66].…”

Chronotherapy in Glioblastoma: state of the art and future perspectives

“…Chronotherapy was explored in melanoma, 29 colorectal, 30 , 31 ovarian cancer, 32 , 33 breast cancer, 34 , 35 non-small-cell lung carcinoma, 36 nasopharyngeal carcinoma, 37 , 38 and glioblastoma 18 , 39 with varying conclusions. Time-dependent administration of treatment in patients with non-small-cell lung carcinoma, 36 melanoma 29 and rats with ovarian cancer 40 prolonged their survival. However, in patients with colorectal cancer, the timed drug administration improved outcomes only of males.…”