Survival of colorectal cancer cell lines treated with paclitaxel, radiation, and 5-FU: effect of TP53 or hMLH1 deficiency.
Clonogenic survival and early cell death during treatment of human colon carcinoma cells were investigated following X-irradiation (IR) alone, IR followed by 5-FU for 24 h, and Taxol administered 24 h before IR and 5F-U. The investigated cell lines were: HCT116, 40-16 clonally derived from HCT116, and two HCT116 variants: N6CHR3 expressing hMLH1, and TP53 null cells denoted HCT116 p53-/-. The objective was to determine efficacy of the combined treatment and to correlate response with constitutive levels of TP53, WAF1, and hMLH1 proteins, as well as with mRNA levels of the apoptosis-related genes survivin, BNIP3, and MYC. At the end of treatment with 5-FU, the proportion of viable cells was between 0.65 and 0.70 for all cell lines. Additional cell loss occurred in 40-16 and HCT116 p53-/- cells following administration of Taxol before IR and 5-FU. Radiation sensitivity was unaffected by combined treatments, except for Taxol, irradiation, and 5-FU sequence in the HCT116 p53-/- and 40-16 cell lines, where radiation sensitivity determined by clonogenic survival curve slopes was doubled or quadrupled, respectively. Under our present experimental conditions, treatment response did not correlate with TP53 or hMLH1 status, but was associated with apoptosis-related genes, most notably BNIP3. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 175-185 (2000).
Kennedy
A S
AS
Department of Radiation Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Harrison
G H
GH
Mansfield
C M
CM
Zhou
X J
XJ
Xu
J F
JF
Balcer-Kubiczek
E K
EK
D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002352:Carrier Proteins; D002470:Cell Survival / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000532:radiotherapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D004791:Enzyme Inhibitors / Q000032:analysis; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins / Q000032:analysis* / Q000187:drug effects / Q000528:radiation effects; D008869:Microtubule-Associated Proteins; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000172:deficiency*; D009687:Nuclear Proteins; D017239:Paclitaxel / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D018714:Radiotherapy, Adjuvant; D000077022:Survivin; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; C501486:MLH1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D000070957:MutL Protein Homolog 1; D017239:Paclitaxel; D005472:Fluorouracil