Regrowth of 5-fluorouracil-treated human colon cancer cells is prevented by the combination of interferon gamma, indomethacin, and phenylbutyrate.
We previously reported that phenylbutyrate (PB), a differentiation agent, retarded the regrowth of fluoropyrimidine-treated HT29 cells to a greater extent in a well-differentiated subclone as compared with a poorly differentiated subclone (Y. Huang and S. Waxman, Clin. Cancer Res., 4: 2503-2509, 1998). To extend these results and to overcome the known heterogeneity of human colon carcinoma (HCC) cells, the effect of cytostatic agents reported to inhibit HCC growth [IFN-alpha and IFN-gamma, indomethacin, and PB alone or in combination] on clonogenicity and HCCs recovery from 5-fluorouracil (FUra) treatment was studied in eight different HCCs. IFN-alpha proved to be ineffective in all eight HCCs, whereas IFN-gamma induced marked growth inhibition in four HCCs that expressed wild-type K-ras. Despite large differences in HCC response to the other individual agents, strong growth inhibition was observed when PB was added in combination with indomethacin. The inhibition was even more pronounced when IFN-gamma was included in the regimen. Most importantly, after treatment with the combination of three agents, the clonogenic potential was severely inhibited (92-100%) in the IFN-gamma-sensitive cell lines, whereas in the IFN-gamma-insensitive cell lines, comparable loss of clonogenecity was obtained when the cells were pretreated with FUra. As known and described in detail, the three cytostatic agents inhibit different processes necessary for cell growth, thus requiring the cells to repair multiple pathways to restore growth. The induction of STAT1 DNA binding activity by IFN-gamma and p21WAF1 by PB, alone or in combination, correlated with growth inhibition and loss of clonogenicity. The finding that the readily reversible growth inhibition and decrease in clonogenicity of FUra-treated HCC are prolonged by subsequent treatment with the three cytostatic agents in all HCCs may be of clinical importance because FUra continues to be the most widely used cytotoxic agent in the treatment of colon carcinoma.
Huang
Y
Y
Rochelle Belfer Chemotherapy Foundation Laboratory, Division of Medical Oncology, New York, New York 10029, USA.
Horvath
C M
CM
Waxman
S
S
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D051546:Cyclooxygenase 2; D053938:DNA Fragmentation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage; D007371:Interferon-gamma / Q000008:administration & dosage; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D010654:Phenylbutyrates / Q000008:administration & dosage; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D050794:STAT1 Transcription Factor; D055502:Secondary Prevention; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D010654:Phenylbutyrates; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D005472:Fluorouracil; D007213:Indomethacin