Modulation of 5-fluorouracil host-toxicity and chemotherapeutic efficacy against human colon tumors by 5-(Phenylthio)acyclouridine, a uridine phosphorylase inhibitor

Abstract

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 combinationin raising and maintaining higher levels of uridine in vivo (Al Safarjalani et al., Cancer Chemo Pharmacol 55:541-551, 2005). Therefore, the combination of PTAU plus uridine can provide a better substitute for the large doses of uridine necessary to rescue or protect from FUra host-toxicities, without the toxic side-effects associated with such doses of uridine. This combination may also allow for the escalation of FUra doses for better chemotherapeutic efficacy against human colon carcinoma while 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.

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

“…This delayed rescue from host toxicity is time dependent and appeared to be optimum at 2 h post-FUra administration. Similar results were obtained when such combinations were used against colon tumors [46]. Further adjustments of the PTAU plus uridine regimen may yield even better results.…”

A novel structural mechanism for redox regulation of uridine phosphorylase 2 activity

“…Previous investigations have molecularly targeted UPP activity to boost plasma and tissue uridine levels in order to rescue normal tissues from cytotoxic fluoronucleotides used in the treatment of neoplastic growths (Pizzorno et al, 1998; Al Safarjalani et al, 2006). The structures of hUPP2 suggest the possibility that this enzyme might be selectively inhibited over hUPP1 by chemically stabilizing the inactive conformation reported herein.…”

“…Subsequently it was shown that certain tumors have increased levels of hUPP1 activity, possibly contributing to the anti-neoplastic tissue selectivity of fluoropyrimidines (Liu et al, 1998; Kawamura et al, 2006). Other research has explored the ability of UPP inhibitors to raise cellular uridine concentrations to mitigate the toxic effects of fluoropyrimidines on healthy tissues during treatment (Chu et al, 1984; Al Safarjalani et al, 2006). Molecules such as 5-benzylacyclouridine (BAU) (Niedzwicki et al, 1982) that selectively block hUPP activity have been analyzed as a means to increase the maximum tolerated dosage and therapeutic index of 5-FU by boosting uridine levels for cyto-protection when properly sequenced (Pizzorno et al, 1998).…”

Active Site Conformational Dynamics in Human Uridine Phosphorylase 1

“…It has also been studied as the molecular target for the design of specific inhibitors intended to boost plasma and tissue uridine levels in order to rescue normal tissues from these cytotoxic compounds [10]. The structure of hUPP1 in complex with 5-FU reported here clarifies several aspects regarding the conformational dynamics of this enzyme, an understanding of which impacts the rational design of better inhibitors with improved affinity and selectivity.…”

“…Other research has shown that some tumours have increased levels of hUPP activity, a finding that may partly explain the tissue selectivity of these chemotherapeutic agents [7], [8]. More recent investigations have explored using hUPP inhibitors to boost cellular uridine concentrations, as a means of limiting the toxic effects of fluoropyrimidine nucleoside exposure to healthy tissues during the course of treatment [9], [10]. Compounds such as 5-benzylacyclouridine (BAU) [11] have been tested for their ability to increase the maximum tolerated dosage and therapeutic index of 5-FU through this uridine-mediated cyto-protective phenomenon [12].…”