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. 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.
Trejo-Becerril
Catalina
C
Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología e Instituto de Investigaciones Biomédicas, UNAM, México City, Mexico.
Pérez-Cárdenas
Enrique
E
Treviño-Cuevas
Homero
H
Taja-Chayeb
Lucía
L
García-López
Patricia
P
Segura-Pacheco
Blanca
B
Chávez-Blanco
Alma
A
Lizano-Soberon
Marcela
M
González-Fierro
Aurora
A
Mariscal
Ignacio
I
Wegman-Ostrosky
Talia
T
Dueñas-González
Alfonso
A
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018196:Carcinoma, Adenosquamous / Q000097:blood / Q000188:drug therapy; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy; D016022:Case-Control Studies; D002945:Cisplatin / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000097:blood*; D004279:DNA, Viral / Q000097:blood*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000008:administration & dosage; D027383:Papillomaviridae / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000097:blood / Q000188:drug therapy; D011379:Prognosis; D051381:Rats; D017208:Rats, Wistar; D014412:Tumor Virus Infections / Q000097:blood / Q000188:drug therapy; D002583:Uterine Cervical Neoplasms / Q000097:blood* / Q000188:drug therapy*; D000093542:Gemcitabine
D004273:DNA, Neoplasm; D004279:DNA, Viral; D009707:Nucleosomes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine