The applications of the novel polymeric fluoropyrimidine F10 in cancer treatment: current evidence

Abstract

F10 is a novel polymeric fluoropyrimidine drug candidate with strong anticancer activity in multiple preclinical models. F10 has strong potential for impacting cancer treatment because it displays high cytotoxicity toward proliferating malignant cells with minimal systemic toxicities thus providing an improved therapeutic window relative to traditional fluoropyrimidine drugs, such as 5-fluorouracil. F10 has a unique mechanism that involves dual targeting of thymidylate synthase and Top1. In this review, the authors provide an overview of the studies that revealed the novel aspects of F10's cytotoxic mechanism and summarize results obtained in preclinical models of acute myeloid leukemia, acute lymphocytic leukemia, glioblastoma and prostate cancer that demonstrate the strong potential of F10 to improve treatment outcomes.

Keywords: acute leukemia; cancer chemotherapy; fluoropyrimidine; glioblastoma; prostate cancer; thymineless death; topoisomerase.

Conflict of interest statement

Financial & competing interests disclosure The authors advise Salzburg Therapeutics, which is involved in commercialization of F10 for cancer treatment and are inventors on issued patents and pending patent applications filed by Wake Innovations. The authors are grateful for support from the Wake Forest Baptist Comprehensive Cancer Center P30 CA012197. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.. Structures of (A) F10 and (B) 5-fluorouracil and schematic of uptake and important metabolites.

F10 is internalized by active transport into acute lymphocytic leukemia cells (see reference [6]) and converted to FdUMP, which inhibits TS, and FdUTP which is incorporated into DNA under thymineless conditions and poisons Top1 to generate DNA double-strand breaks. 5-FU enters both malignant and nonmalignant cells by passive diffusion and is converted to FUMP (a). FUMP is inefficiently converted to FdUMP (b, c). 5-FU also can be converted to FdUMP (d, e). 5-FU is also catabolized to FBAL, which causes cardio- and neuro-toxicity. The direct conversion of F10 to DNA-directed metabolites enhances DNA damage and contributes to anticancer activity while causes mainly RNA damage that contribute to systemic toxicities. 5-FU: 5-fluorouracil; a: UMPS; b: UMPK; c: RNR; d: TP; e: TK.

Figure 2.. F10 displays strong antileukemic activity with minimal systemic toxicities.

(A) F10 confers a survival benefit equivalent to the combination of Ara-C and doxorubicin. C57/Bl6 mice were sublethally irradiated to 4.5 Gy and injected with an MLL-ENL and Flt3 ITD syngeneic AML. Once engraftment was established by bioluminescence imaging, mice were treated with either saline (control), F10 at 300 mg/kg (FdUMP [10]), 5-FU at 121 mg/kg (5-FU) or cytarabine at 125 mg/kg plus doxorubicin at 3.75 mg/kg (Ara-Dox) on days 1, 3, 5 and 7. (B) F10 is active against multiple ALL models in vivo. Survival of C57Bl/6 mice injected with syngeneic, Ph+ B-cell ALL model and treated with saline or F10 at 300 mg/kg every other day for 4, 6 or 9 doses as indicated. (C) Survival of ALL xenograft bearing mice from time of injection treated with saline or F10 at 300 mg/kg every other day ×5 doses as indicated. All p-values were derived from log-rank tests. (D–G) F10 (F) causes much less bone marrow toxicity than 5-FU (D) or AraC-Dox (E) – regions of hypocellularity are indicated with yellow arrows. Panel (G) is vehicle-treated control. Drug dosing was the same as in panel (A). 5-FU: 5-fluorouracil; ALL: Acute lymphocytic leukemia; AML: Acute myeloid leukemia. (A & D–G) Data taken from [5]; (B & C) data taken from [6].