title: Human DNA damage checkpoints and their relevance to soft tissue sarcoma.
abstract: Soft tissue sarcoma (STS) is a malignant neoplasm, arising in mesenchymal tissues, that is difficult to treat clinically because it can be highly resistant to chemo-radiotherapy. At present, the mechanism of that resistance remains unclear. Cell cycle checkpoints engender strict control of cell proliferation, arresting the cell cycle to provide time for repair or apoptosis when DNA damage is induced by unprogrammed extrinsic events. These pathways involve at least two checkpoints: one at the G1/S transition and one at the G2/M transition. The p53 gene, which is mutated in several malignant tumors, plays an important role in DNA repair at the G1/S transition; however, there is little information on the G2/M checkpoint in STS. In the present study, several proteins (phospho-p53, -cdc25, -cdc2, -Chk1 and -Chk2) involved in checkpoint pathways were investigated using immunohistochemistry in STS specimens. Most STSs maintain a well-preserved G2/M checkpoint despite the loss of the G1/S checkpoint (phospho-p53: 4.9% (2/41); -cdc25: 41% (17/41); -cdc2: 61% (25/41); -Chk1: 29% (12/41); -Chk2: 46% (19/41)). Furthermore, in a postoperative chemotherapy case the number of cells positive for phospho-cdc25 and -Chk2 was higher in a recurrent tumor than in the primary tumor (n = 7, P = 0.046 < 0.05, Wilcoxon signed-ranks test). These findings indicate that the G2/M checkpoint pathway is well preserved and might contribute to the chemotherapeutic resistance associated with STS.
authors.affiliation: Department of Orthopedic Surgery, Tokyo Medical University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hattori
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ishida
authors.forename: Koutarou
authors.initials: K
authors.lastname: Shinmura
authors.forename: Shuzou
authors.initials: S
authors.lastname: Nagai
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mukai
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Imakiire
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D004249:DNA Damage; D004273:DNA, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins