Use of E. coli Purine Nucleoside Phosphorylase in the Treatment of Solid Tumors

Abstract

Background: The selective expression of non-human genes in tumor tissue to activate non-toxic compounds (Gene Directed Prodrug Enzyme Therapy, GDEPT) is a novel strategy designed for killing tumor cells in patients with little or no systemic toxicity. Numerous non-human genes have been evaluated, but none have yet been successful in the clinic.

Methods: Unlike human purine nucleoside phosphorylase (PNP), E. coli PNP accepts adenine containing nucleosides as substrates, and is therefore able to selectively activate non-toxic purine analogs in tumor tissue. Various in vitro and in vivo assays have been utilized to evaluate E. coli PNP as a potential activating enzyme.

Results: We and others have demonstrated excellent in vitro and in vivo anti-tumor activity with various GDEPT strategies utilizing E. coli PNP to activate purine nucleoside analogs. A phase I clinical trial utilizing recombinant adenoviral vector for delivery of E. coli PNP to solid tumors followed by systemic administration of fludarabine phosphate (NCT01310179; IND# 14271) has recently been completed. In this trial, significant anti-tumor activity was demonstrated with negligible toxicity related to the therapy. The mechanism of cell kill (inhibition of RNA and protein synthesis) is distinct from all currently used anticancer drugs and all experimental compounds under development. The approach has demonstrated excellent ability to kill neighboring tumor cells that do not express E. coli PNP, is active against non-proliferating and proliferating tumors cells (as well as tumor stem cells, stroma), and is therefore very effective against solid tumors with a low growth fraction.

Conclusion: The unique attributes distinguish this approach from other GDEPT strategies and are precisely those required to mediate significant improvements in antitumor therapy.

Conflict of interest statement

Conflict of Interest

Drs. Parker and Sorscher have a significant equity position in PNP Therapeutics, which has licensed the patents concerning the use of E. coli PNP for the treatment of cancer.

Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Figures

Figure 1

Conversion of MeP-dR by E. coli PNP to MeP

Figure 2

Structures of F-araA, F-dAdo, and F-Ade

Figure 3

Metabolism of F-araAMP in cell expressing E. coli PNP

Figure 4

Effect of F-araAMP and F-dAdo on tumors expressing high levels of E. coli PNP Mice bearing subcutaneous D54 xenografts expressing E. coli PNP (126,000 nmoles/mg-hr) were treated with intraperitoneal F-dAdo or F-araAMP at the doses shown five times daily for 3 consecutive days beginning on Day 13. Six mice were treated per. Tumor size was measured using calipers, and the median tumor weight was plotted.

Figure 5

Demonstration of dose dependence of F-araAMP antitumor activity and in vivo bystander activity against D54 xenografts Mice bearing subcutaneous D54 xenografts in which 10% of the cells express E. coli PNP (14,000 nmoles/mg-hr) were treated with intraperitoneal F-araAMP at the doses shown five times daily for 3 consecutive days beginning on Day 13. Six mice were treated per group. Tumor size was measured using calipers, and the median tumor weight was plotted.