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

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2021 Jun 3

PMID 34079283

Citations 2

Authors

Galina Kireeva

Ekaterina Gubareva

Mikhail Maydin

Vladislav Osetnik

Stepan Kruglov

Andrey Panchenko

Anastasia Dorofeeva

Margarita Tyndyk

Elena Fedoros

Vladimir Anisimov

Affiliations

Soon will be listed here.

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, <0.001) and in HIPEC at ZT12 32.0 days (95% CI 28.0-37.0, <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.

Citing Articles

Evaluation of the Effect of Different Inhalation Agents on Ovaries with Hyperthermic Intraperitoneal Chemotherapy: An Experimental Study.

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

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