Tumor specific conversion of a pyrimidine antimetabolite

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• Significant variations in the activity of 5 -deoxyribofuranosyl-5-fluorouracil (5 -dFUR) and 5-fluoro-2 -deoxyuridine (FUdR) were observed across four tumor cell lines.
• Understanding the metabolic conversion of these nucleoside analogs to the active cytotoxic metabolite, 5-fluorouracil (5-FU), is crucial for explaining differential drug responses.

Purpose of the Study:

• To investigate the enzymatic conversion rates of 5 -dFUR and FUdR to 5-FU in various tumor homogenates.
• To compare these conversion rates with the endogenous conversion of uridine to uracil in both tumor and liver tissues.
• To correlate enzymatic activity with the observed in vivo and in vitro sensitivity or resistance to 5 -dFUR.

Main Methods:

• Measurement of nucleoside conversion rates to 5-FU in four tumor lines and normal liver homogenates.
• Assay of pyrimidine nucleoside phosphorylase (PNP) activity.
• Comparison of conversion rates of 5 -dFUR and FUdR with uridine to uracil conversion.

Main Results:

• Tumor tissues sensitive to 5 -dFUR exhibited high pyrimidine nucleoside phosphorylase activity.
• Conversion rates of uridine and 5 -dFUR were significantly lower in 5 -dFUR-insensitive tumors and normal liver homogenates.
• A direct correlation was observed between high PNP activity and efficient conversion of 5 -dFUR to 5-FU.

Conclusions:

• Pyrimidine nucleoside phosphorylase activity is a key determinant of 5 -dFUR and FUdR efficacy.
• Higher PNP levels in sensitive tumors facilitate greater conversion to the cytotoxic 5-FU metabolite.
• These enzymatic differences likely contribute to the observed variations in drug response in vitro and in vivo.