Interferon induces thymidine phosphorylase/platelet-derived endothelial cell growth factor expression in vivo.
The enzyme/cytokine thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) has diverse functions within cells, including the regulation of steady-state thymidine levels, the conversion of the cancer chemotherapeutic agent 5-fluorouracil (FUra) to an active metabolite, and the mediation of angiogenesis in normal and malignant cells. Although the levels of TP/PD-ECGF vary substantially among different tissues and are generally found to be elevated in tumors, little is known about the control of its expression in vivo in humans. In this study, peripheral blood mononuclear cells were obtained from patients prior to and during treatment with IFN and FUra and analyzed for TP/PD-ECGF expression. Sixteen of 21 patients (76%) exhibited an average 3-4-fold increase of TP/PD-ECGF protein levels after treatment with either IFN-alpha or-beta, with the remaining patients having either a decrease (four patients) or no change (one patient) at the sampling times examined. Expression in vivo increased rapidly within 1-2 h of IFN treatment and remained elevated for up to 48 h after its administration. The increase in TP/PD-ECGF protein was accompanied by a concomitant increase in TP/PD-ECGF mRNA levels. TP/PD-ECGF mRNA expression in cells in vitro was induced by IFN but not by pharmacologically relevant concentrations of FUra, suggesting that the IFN was responsible for the induction seen in the patients. This study demonstrates that IFN induces TP/PD-ECGF expression in vivo by regulation of the level of mRNA expression.
Makower
D
D
Department of Oncology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10467, USA.
Wadler
S
S
Haynes
H
H
Schwartz
E L
EL
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001792:Blood Platelets / Q000502:physiology*; D002986:Clinical Trials as Topic; D003110:Colonic Neoplasms; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D004790:Enzyme Induction; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D000077190:Interferon alpha-2; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016898:Interferon-alpha / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D009369:Neoplasms / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000627:therapeutic use; D013939:Thymidine Phosphorylase / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000068576:Interferon beta-1b; D016899:Interferon-beta; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; D006918:Hydroxyurea; D000068556:Interferon beta-1a