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Delivery of high levels of anti-proliferative nucleoside triphosphates to CYP3A-expressing cells as a potential treatment for hepatocellular carcinoma

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Abstract

Purpose

Hepatocellular carcinoma (HCC) is a life-threatening condition with only one drug treatment regimen approved for use. Oncolytic nucleosides are minimally effective against HCC putatively because of their inability to achieve cytotoxic levels of the active metabolite [nucleoside triphosphate (NTP)] in tumor cells at doses that are well tolerated. The aim of our studies was to explore the utility of CYP3A-activated prodrugs of cytarabine and fludarabine monophosphate for the treatment of HCC.

Methods

Prodrugs of cytarabine and fludarabine monophosphates were evaluated for their ability to safely achieve NTP levels in the liver of normal mice that are cytotoxic to hepatoma cells.

Results

While therapeutic levels of NTPs are achieved in the livers of normal rodents after administration of the prodrugs, only MB07133 achieved these levels whithout exhibiting signs of liver toxicity or myelosuppression.

Conclusions

As the levels of araCTP achieved in the liver at therapeutic doses are only toxic to proliferating cells (such as those in HCC tumors), but not the non-proliferative adjacent tissue, MB07133 treatment has the potential to be both efficacious and well tolerated in HCC patients.

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Acknowledgments

The authors would like to thank Paul Rolzin and Barbara Treash-Osio for their technical assistance in the conduct of the studies described herein. We would also like to thank Dr. Paul D. van Poelje for editorial assistance and scientific input throughout the conduct of these studies. We would like to acknowledge the efforts of Dr. Sanna Rosengren whose initial work on this project lead to the discoveries described herein.

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Correspondence to Deidre A. MacKenna.

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MacKenna, D.A., Montag, A., Boyer, S.H. et al. Delivery of high levels of anti-proliferative nucleoside triphosphates to CYP3A-expressing cells as a potential treatment for hepatocellular carcinoma. Cancer Chemother Pharmacol 64, 981–991 (2009). https://doi.org/10.1007/s00280-009-0953-5

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