HPV16-E7 expression causes fluorodeoxyuridine-mediated radiosensitization in SW620 human colon cancer cells.
We have reported that HT29 colon cancer cells, which are radiosensitized by fluorodeoxyuridine (FdUrd), exhibit a greater increase in cyclin E-dependent kinase activity and progress further into S phase in the presence of FdUrd than do SW620 colon cancer cells, which are only minimally sensitized by this drug (Cancer Res 56: 3203, 1996). Although these findings suggested that the ability to progress into S phase in the presence of FdUrd permits cells to be radiosensitized, we wished to test this hypothesis by attempting to drive SW620 human colon cells into S phase by transducing them with the HPV16-E7 gene. Two-parameter flow cytometry showed that E7-transduced cells progressed through S phase after radiation and FdUrd treatment more rapidly than SW620 parental cells. We found that E7-transduced SW620 cells were significantly radiosensitized by FdUrd (100 nmol/L, 14 hours) with an enhancement ratio for 2 clones of 1.47 +/- 0.03 and 1.51 +/- 0.14, compared with 1.24 +/- 0.04 in SW620 parental cells. These data strongly support the hypothesis that dysregulation of S-phase progression is an important factor in FdUrd-mediated radiosensitization.
Axelson
M D
MD
Department of Radiation Oncology, University of Michigan, Ann Arbor, USA.
Davis
M A
MA
Ethier
S P
SP
Lawrence
T S
TS
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D019927:Cyclin E; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D005467:Floxuridine / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D012190:Retroviridae / Q000235:genetics; D016196:S Phase / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D013940:Thymidylate Synthase / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D019927:Cyclin E; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D005467:Floxuridine; D013940:Thymidylate Synthase; D018844:Cyclin-Dependent Kinases