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Cancer Chemotherapy by Deoxynucleotide Depletion and E2F-1 Elevation

¹ ArQule Biomedical Institute, ArQule Inc., Woburn, Massachusetts; ² Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan; and ³ Dana-Farber Cancer Institute, Boston, Massachusetts

Requests for reprints: Arthur B. Pardee, Department of Cell Growth, Dana-Farber Cancer Institute, D-810, 44 Binney Street, Boston, MA 02115. Phone: 617-632-3372; Fax: 617-632-4680; E-mail: arthur_pardee{at}dfci.harvard.edu.

We propose that the lethality of commonly used anticancer drugs, e.g., methotrexate and cis-platinum are due, at least in part, to an increase of the E2F-1–mediated apoptotic cascade. The drugs directly or indirectly decrease deoxynucleoside triphosphates. The E2F family acts to provide control of S phase by transcribing genes required for deoxynucleoside triphosphate and DNA synthesis. Thus, a mechanism for control of E2F-1 is essential, a signal safeguarding against aberrant or uncontrolled cell proliferation. We have proposed a feedback control by NTPs that down-regulates E2F-1. Here, we provide evidence in support of this hypothesis.

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