Circulating nucleosomes and response to chemotherapy: An in vitro, in vivo and clinical study on cervical cancer patients

It is known that cell‐free DNA circulates in plasma/serum of patients with cancer and that part of this DNA circulates as nucleosomes that can be quantified by ELISA. We analyzed the effect of tumor and chemotherapy upon the levels of nucleosomes in vitro, in vivo and in cervical cancer patients. Th...

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Published in:	International journal of cancer Vol. 104; no. 6; pp. 663 - 668
Main Authors:	Trejo‐Becerril, Catalina, Pérez‐Cárdenas, Enrique, Treviño‐Cuevas, Homero, Taja‐Chayeb, Lucía, García‐López, Patricia, Segura‐Pacheco, Blanca, Chávez‐Blanco, Alma, Lizano‐Soberon, Marcela, González‐Fierro, Aurora, Mariscal, Ignacio, Wegman‐Ostrosky, Talia, Dueñas‐González, Alfonso
Format:	Journal Article
Language:	English
Published:	New York Wiley Subscription Services, Inc., A Wiley Company 10-05-2003 Wiley-Liss
Subjects:	Adenocarcinoma - blood Adenocarcinoma - drug therapy Adult Aged Animals Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Carcinoma, Adenosquamous - blood Carcinoma, Adenosquamous - drug therapy Carcinoma, Squamous Cell - blood Carcinoma, Squamous Cell - drug therapy Case-Control Studies cervical cancer Chemotherapy circulating nucleosomes Cisplatin - therapeutic use Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives DNA, Neoplasm - blood DNA, Viral - blood ELISA Enzyme-Linked Immunosorbent Assay Female HeLa Cells Humans In Vitro Techniques Medical sciences Mice Mice, Nude Middle Aged neoadjuvant chemotherapy Neoadjuvant Therapy Neoplastic Cells, Circulating - metabolism Nucleosomes - metabolism Organoplatinum Compounds - administration & dosage Paclitaxel - administration & dosage Papillomaviridae - pathogenicity Papillomavirus Infections - blood Papillomavirus Infections - drug therapy Pharmacology. Drug treatments Prognosis Rats Rats, Wistar Tumor Virus Infections - blood Tumor Virus Infections - drug therapy Uterine Cervical Neoplasms - blood Uterine Cervical Neoplasms - drug therapy Antineoplastic agent Gemcitabine Rat Uterine cervix Oxaliplatin Serum Pyrimidine nucleoside Non small cell carcinoma Platinum II Complexes Drug combination Treatment efficiency Nucleosome Rodentia Malignant tumor In vitro Cisplatin Female genital diseases In vivo Vertebrata Alkylating agent Chemotherapy Mammalia Treatment Antimetabolic Mouse Animal Fluorine Organic compounds Uterine cervix diseases
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Summary:	It is known that cell‐free DNA circulates in plasma/serum of patients with cancer and that part of this DNA circulates as nucleosomes that can be quantified by ELISA. We analyzed the effect of tumor and chemotherapy upon the levels of nucleosomes in vitro, in vivo and in cervical cancer patients. The levels of nucleosomes pre‐ and post‐treatment were correlated with response in 11 patients receiving chemotherapy. Nucleosomes were determined in nude mice treated with or without cisplatin and carrying tumors generated with HeLa cells, and in the cell lysate and supernatant of HeLa cells exposed to cisplatin in culture. In addition, nucleosomes were determined at different time points in patients and in rats receiving chemotherapy. Nucleosomes were higher in patients that controls (1,760 vs. 601, p = 0.0001). After 24 hr of treatment with oxaliplatin and gemcitabine, the levels decreased in 6 patients of whom 5 had response. Nucleosome levels differed between mice xenografted and not xenografted (765 vs. 378, p = 0.001) and between xenografted treated with or without cisplatin (650 vs. 765, p = 0.010), but not in tumor‐free animals treated and untreated with cisplatin (378 vs. 379, p = 0.99). In vitro, nucleosomes reached at peak 8 hr in cell lysates to decrease thereafter, whereas in supernatant, levels continued to increase up to 24 hr. Serial determination of nucleosomes in patients showed a rise within 6–12 hr and then a reduction to below the basal at 24 hr. In rats, nucleosomes had no major changes in those receiving oxaliplatin or the triple combination of cisplatin, gemcitabine and paclitaxel as compared to untreated controls. An overdose of this triple combination produced a transient elevation of almost 1,000 AU over the basal. Our results demonstrate that most of circulating nucleosomes originate from the tumor and that chemotherapy produces an early rise most likely due to tumor apoptosis and that nucleosomes are rapidly cleared from circulation. On the contrary, chemotherapy within the therapeutic range of doses has no effect on nucleosome levels in healthy mice and rats. This data suggests that the determination of circulating nucleosomes pre‐ and post‐treatment could be a useful test to predict response to chemotherapy in cancer patients. © 2003 Wiley‐Liss, Inc.
Bibliography:	Fax: +525‐55‐56280432 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0020-7136 1097-0215
DOI:	10.1002/ijc.11003