Cisplatin Reduces the Frequencies of Radiotherapy-Induced Micronuclei in Peripheral Blood Lymphocytes of Patients with Gynaecological Cancer: Possible Implications for the Risk of Second Malignant Neoplasms.

Aneta Węgierek-Ciuk,Pamela Akuwudike,Andrzej Wojcik,Halina Lisowska,Piotr Kędzierawski,Anna Lankoff,Lovisa Lundholm

doi:10.3390/cells10102709

Abstract

Gynaecologic cancers are common among women and treatment includes surgery, radiotherapy or chemotherapy, where the last two methods induce DNA damage in non-targeted cells like peripheral blood lymphocytes (PBL). Damaged normal cells can transform leading to second malignant neoplasms (SMN) but the level of risk and impact of risk modifiers is not well defined. We investigated how radiotherapy alone or in combination with chemotherapy induce DNA damage in PBL of cervix and endometrial cancer patients during therapy. Blood samples were collected from nine endometrial cancer patients (treatment with radiotherapy + chemotherapy—RC) and nine cervical cancer patients (treatment with radiotherapy alone—R) before radiotherapy, 3 weeks after onset of radiotherapy and at the end of radiotherapy. Half of each blood sample was irradiated ex vivo with 2 Gy of gamma radiation in order to check how therapy influenced the sensitivity of PBL to radiation. Analysed endpoints were micronucleus (MN) frequencies, apoptosis frequencies and cell proliferation index. The results were characterised by strong individual variation, especially the MN frequencies and proliferation index. On average, despite higher total dose and larger fields, therapy alone induced the same level of MN in PBL of RC patients as compared to R. This result was accompanied by a higher level of apoptosis and stronger inhibition of cell proliferation in RC patients. The ex vivo dose induced fewer MN, more apoptosis and more strongly inhibited proliferation of PBL of RC as compared to R patients. These results are interpreted as evidence for a sensitizing effect of chemotherapy on radiation cytotoxicity. The possible implications for the risk of second malignant neoplasms are discussed.

Highlights

Introduction distributed under the terms andDue to improvements in cancer therapy and general increase of life expectancy, the prevalence of cancer survivors is increasing [1]
Using the MN assay in peripheral blood lymphocytes (PBL) as a biomarker of cancer risk, we investigated the potential modulatory effect of chemotherapy on radiotherapyrelated risk of second malignant neoplasms (SMN)
Ninety-five percent confidence intervals of the mean are shown as blue boxes for MN frequencies induced by therapy alone and by red boxes for MN frequencies induced by therapy plus 2 Gy ex vivo irradiation

Summary

Introduction

Introduction distributed under the terms andDue to improvements in cancer therapy and general increase of life expectancy, the prevalence of cancer survivors is increasing [1]. An intriguing question regarding the risk of radiotherapy-induced SMN is related to the shape of the dose–response curve. The shape of the dose–response curve for radiation-induced cancer is bell-shaped [3]. Such response is observed in animals following whole body exposure [4] and among the survivors of the Hiroshima and Nagasaki atomic bombings [4]. Three parallel models exist that describe the relationship between the radiotherapy dose to normal tissue and the risk of cancer: the linear model—assuming a constant increase of risk with dose, the plateau model—assuming a plateau effect, and the competition model—assuming a decline of risk at high doses [5,6]. Investigations on the location of SMN with respect to the therapeutic dose received by a primary tumour failed to show a clear dose–response relationship [7,8]

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