Retroviral IFN-alpha gene transfer combined with gemcitabine acts synergistically via cell cycle alteration in human pancreatic carcinoma cells implanted orthotopically in nude mice.
Standard chemotherapy for pancreatic carcinoma is based on the use of gemcitabine. The clinical benefit of interferon-alpha (IFN-alpha) in advanced pancreatic cancer has been shown. However, it has been demonstrated that to be effective, there is a need for a constant amount of IFN-alpha at the site of the tumor. Therefore, we examined transfection of the human pancreatic cancer cell line DAN-G with a retrovirus encoding for IFN-alpha and the effect of IFN-alpha gene expression alone or in combination with gemcitabine on growth inhibition of DAN-G pancreatic cancer cells in vitro and in vivo in orthotopically implanted DAN-G cells in nude mice. DAN-G cells could be efficiently transfected retrovirally by the human IFN-alpha gene and significantly enhanced the levels of IFN-alpha mRNA. In vitro gemcitabine led to an alteration of G1/S phase progression in transduced as well as untransduced cells, whereas IFN-alpha led to a significant decrease in cell viability in the transduced cells via delay in the progression of the S phase but no alteration of G1/S phase progression. In vivo, tumor volume in mice was reduced significantly with gemcitabine combined with IFN-alpha (76% +/- 8.3%) compared with gemcitabine alone (62.9% +/- 7.3%) or IFN-alpha alone (24.4% +/- 5.2%) compared with untreated animals. We conclude that gemcitabine and IFN-alpha concomitantly inhibited tumor cell proliferation significantly.
Medizinische Klinik und Poliklinik I, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany. carsten.ziske@ukb.uni-bonn.de
Carsten
C
Ziske
Srinivas
S
Nagaraj
Angela
A
Märten
Marcus
M
Gorschlüter
John
J
Strehl
Tilman
T
Sauerbruch
Nader G
NG
Abraham
Ingo G H
IG
Schmidt-Wolf
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D012190:Retroviridae / Q000235:genetics*; D019076:Transgenes / Q000235:genetics; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D018076:DNA, Complementary; D016898:Interferon-alpha; D003841:Deoxycytidine; D000093542:Gemcitabine