Interferon alpha and 5'-deoxy-5-fluorouridine in colon cancer: effects as single agents and in combination on growth of xenograft tumours.
Interferon-alpha (IFN-alpha) enhances the activity of the 5-fluorouracil (5-FU) prodrug 5'-deoxy-5-fluorouridine (5'-dFUrd) in colorectal cancer cells in vitro by upregulating the enzyme pyrimidine nucleoside phosphorylase (PNPase), which is responsible for converting 5'-dFUrd to 5-FU. We examined whether such enhancement also occurs in vivo using human colorectal xenografts in nude mice. The Co-115 line has high basal levels of PNPase and the enzyme level was increased in tumours from mice treated for 3 weeks with 50,000 IU/day (5 days/week) of IFN-alpha A/D. The prodrug 5'-dFUrd (200 mg/day, 5 days/week) had a much greater antitumour activity than 5-FU had when it was used at an approximately equitoxic dose (20 mg/day, 5 days/week). However, because of the high activity of 5'/dFUrd as a single agent, no enhancement by IFN-alpha A/D was observed. Studies on xenografts of WiDr cells indicated that this line is much less sensitive to 5'-dFUrd. However, treatment of animals with IFN-alpha A/D at doses of 75,000 IU/day or 150,000 IU/day resulted in significant inhibition of WiDr tumour growth. Combination treatment with 75 mg/kg/day or 150 mg/kg/day of 5'-dFUrd resulted in enhanced antitumour activity, particularly at the higher dose of IFN-alpha A/D. Synergy of this drug combination was confirmed by isobologram analysis. Analysis of PNPase levels in WiDr tumours, excised from mice treated with IFN-alpha A/D, demonstrated that the enzyme activity was increased by IFN-alpha in a dose-dependent manner. Slight increases were also seen in normal liver and intestine from the same animals. Our results indicate that modulation of converting enzymes for anticancer prodrugs by cytokines could be a novel therapeutic strategy for combination therapy of colorectal cancer.
Laurent
P L
PL
Swiss Institute for Experimental Cancer Research, Epalinges.
Tevaearai
H T
HT
Eliason
J F
JF
Givel
J C
JC
Odartchenko
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D005467:Floxuridine / Q000627:therapeutic use*; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007370:Interferon Type I / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010430:Pentosyltransferases / Q000378:metabolism; D011355:Prodrugs / Q000627:therapeutic use*; D057845:Pyrimidine Phosphorylases; D011994:Recombinant Proteins; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D007370:Interferon Type I; D011355:Prodrugs; D011994:Recombinant Proteins; D005467:Floxuridine; D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; D005472:Fluorouracil; C025034:doxifluridine