Biologic activity of polyethylene glycol12000-interferon-alpha2b compared with interferon-alpha2b: gene modulatory and antigrowth effects in tumor cells.
The relative activities of interferon-alpha2b (IFN-alpha2b) and polyethylene glycol(12000)-IFN-alpha2b (PEG-IFN-alpha2b) were assessed in cell culture studies using WM9 melanoma or ACHN renal cell carcinoma cell lines. Interferon-alpha2b and PEG-IFN-alpha2b had identical antiproliferative activities when tested in cell proliferation studies conducted with equivalent antiviral units of each IFN preparation. Neither IFN formulation was effective in inducing apoptosis in WM9 melanoma cells, but both increased slightly the percentage of ACHN cells undergoing apoptosis as assessed by Annexin V staining. Interferon-alpha2b and PEG-IFN-alpha2b both activated signal transducer and activator of transcription complexes, and the duration of complex activation was similar for both IFN formulations. Induction of different IFN-stimulated genes was assessed by Northern blotting and the quantitative real-time reverse transcription-coupled polymerase chain reaction (RT-PCR) in WM9 melanoma, ACHN renal cell carcinoma, U937 lymphoma, and MOLT-4 and Mono Mac 6 leukemia cell lines. Interferon-alpha2b and PEG-IFN-alpha2b had equivalent gene-modulatory activities within each of these tumor cell lines, although cell line-specific induction patterns were observed. When compared with the antiviral 50% inhibitory concentration (IC(50)) values, the dose-dependent gene expression data correlated with cell sensitivity to IFN treatment. Together, the drug comparability and cell sensitivity data suggest a predictive relation between dose, time, antiviral activity, and gene transcription effects. Therefore, although the specific activity of IFN-alpha2b is approximately three times greater than PEG-IFN-alpha2b, the two preparations have identical in vitro biologic activities when applied to cells at equivalent antiviral units.
Vyas
Keyur
K
Cleveland Clinic Taussig Cancer Center and Lerner Research Institute, Ohio, USA.
Brassard
Diana L
DL
DeLorenzo
Marc M
MM
Sun
Yaping
Y
Grace
Michael J
MJ
Borden
Ernest C
EC
Leaman
Douglas W
DW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a