G2/M cell cycle checkpoint is functional in cervical cancer patients after initiation of external beam radiotherapy.
OBJECTIVE
To investigate changes in cancer of the uterine cervix during radiotherapy (RT) with respect to G2/M transition in relation to tumor cell apoptosis and changes in the tumor vasculature in cervical carcinoma.


METHODS
A total of 40 consecutive patients with Stage IIA-IIIB cervical cancer underwent RT without any chemotherapy. Tumor biopsy was obtained before RT and after five fractions of 1.8 Gy. The tumor samples were stained for cyclin B1, cdc2, and Ki-67, the apoptotic index, using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining. The tumor vasculature density was assessed. In 38 cases, the tissue samples were informative.


RESULTS
Cyclin B1 was positive in all biopsies before and after initiation of RT, and staining for cdc2 was positive in 35 (92%) of 38 biopsies before and 33 (87%) of 38 after 1 week of RT. Nuclear staining for cyclin B1 was observed in 92% of patients, staining an average of 15% of cells before RT. After initiating RT, 73% of patients showed positive staining on about 5% of tumor cells (p < 0.01). Nuclear staining for cdc2 was detected in 89% of patients, staining an average of 21% of cells before RT. After initiating RT, 79% of patients showed positive staining on 9% of cells (p < 0.01). The apoptotic index of the tumor cells increased after initiating RT, and a slight decrease in the vascular density after 1 week of RT was noted (p = 0.08). Changes in G2/M were associated with the clinical response, but changes in apoptosis or tumor vasculature were not.


CONCLUSIONS
RT leads to significant changes in the cell cycle in cervical cancer indicating intact G2/M checkpoint function. Targeting G2/M with compounds interfering with G2/M transition may further enhance the effect of RT in cervical cancer patients.
Cerciello
Ferdinando
F
Department of Radiation Oncology, Zurich University Hospital, University of Zurich, Zurich, Switzerland.
Hofstetter
Barbara
B
Fatah
Sherweif Abdel
SA
Zaghloul
Mohamed
M
Odermatt
Bernhard
B
Bodis
Stephan
S
Varga
Zsuzsanna
Z
Pruschy
Martin
M
Ciernik
Ilja F
IF
D000328:Adult; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000032:analysis*; D002467:Cell Nucleus / Q000737:chemistry; D019926:Cyclin B / Q000032:analysis*; D056744:Cyclin B1; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D016195:G2 Phase / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D008938:Mitosis / Q000502:physiology / Q000528:radiation effects*; D011879:Radiotherapy Dosage; D012074:Remission Induction; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000737:chemistry* / Q000532:radiotherapy*
C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D019394:Ki-67 Antigen; D016203:CDC2 Protein Kinase