Potent combination therapy for human breast tumors with high doses of 5-fluorouracil: remission and lack of host toxicity

The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in reducing 5-fluorouracil (FUra) host toxicity and enhancing its chemotherapeutic efficacy against human breast tumors. PTAU is a potent and specific inhibitor of uridine phosphorylase (UP, EC 2.4.2.3), the enzyme responsible for uridine catabolism. SCID mice bearing MDA-MB-468 and MCF-7 human breast tumors were injected intraperitoneally with FUra (50, 200 or 300 mg/kg) on days 17, 24, and 31 after tumor cell inoculation. PTAU (120 mg/kg), uridine (1,320 mg/kg), or their combination was administered orally two or 4 h after FUra injection. Another four administrations of PTAU plus uridine were given every 8 h after the first treatment with PTAU plus uridine. Survival and body weight were used to evaluate host toxicity. Tumor weight was used to evaluate the efficacy of the drugs on tumor growth. The mice were monitored for 38 days. Administration of the maximum tolerated dose (50 mg/kg) of 5-fluorouracil (FUra) to SCID mice bearing human breast MDA-MB-468 and MCF-7 adenocarcinoma tumor xenografts reduced tumor weight by 59 and 61%, respectively. Administration of 200 mg/kg FUra resulted in 100% mortality. Oral administration of uridine (1,320 mg/kg) alone, 2 h following the administration of 200 mg/kg FUra, did not rescue from FUra host toxicity as all the mice died. Administration of 120 mg/kg PTAU resulted in partial rescue from this lethal dose of FUra as 38% of inoculated mice survived and the tumor weights were reduced by approximately 67%. Coadministration of PTAU plus uridine resulted in complete rescue from the toxicity of FUra. All of the mice survived, and MDA-MB-468 and MCF-7 tumor weights were reduced by 97% and total remission, respectively. Doubling the FUra treatment dose to 400 mg/kg in the MDA-MB-468 inoculated mice, with the administration of the adjuvant combination treatment of PTAU plus uridine, was unsuccessful in rescuing from FUra toxicity as all the mice died. Lowering the dose of FUra to 300 mg/kg, under the same conditions, resulted in 67% mice survival, and the MCF-7 tumor weights were reduced by 100%. Treatment with uridine alone did not protect from FUra toxicity at 200, 300, and 400 mg/kg as all of the mice died. At the higher dose of 300 and 400 mg/kg FUra, PTAU alone had no rescuing effect. There was no significant difference between MDA-MB-468 and MCF-7 in their response to the different regimens employed in this study in spite of the fact that MDA-MB-468 is estrogen receptor negative while MCF-7 is estrogen receptor positive. The present results demonstrate that the combination of PTAU plus uridine represents an exceptionally efficient method in increasing FUra chemotherapeutic efficacy while minimizing its host toxicity. The efficiency of the PTAU plus uridine combination can be attributed to the extraordinary effectiveness of this combination treatment in raising and maintaining higher levels of uridine in vivo (Al Safarjalani et al. in Cancer Chemo Pharmacol 55:541–551, 2005). Therefore, the combination of PTAU plus uridine can provide a better substitute for the massive doses of uridine necessary to rescue or protect from FUra host-toxicities, without the toxic side effects associated with such doses of uridine. The combination may also allow the escalation of FUra doses for better chemotherapeutic efficacy against human breast carcinoma, with the possibility of avoiding FUra host-toxicities. Alternatively, the combination of PTAU and uridine may be useful as an antidote in the few cases when cancer patients receive a lethal overdose of FUra.