Depletion of Nicotinamide Adenine Dinucleotide in Normal and Xeroderma Pigmentosum Fibroblast Cells by the Antitumor Drug CC-1065

Myron K. Jacobson, Debra Twehous, Laurence H. Hurley

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

CC-1065 is an extremely potent antitumor antibiotic that forms a well-defined adduct with DNA in which the molecule lies within the minor groove and is covalently attached through N3 of adenine. Addition of CC-1065 to human fibroblast cells produced a prolonged depletion of the nicotinamide adenine dinucleotide (NAD) pool even at extremely low drug concentrations (0.01 μg/mL). The depletion of NAD by CC-1065 was blocked by 3-aminobenzamide, which is consistent with a NAD depletion mechanism involving poly-(ADP-ribose) synthesis in response to a repair-induced DNA strand breakage event. Significantly, similar extents of NAD depletion were also evident in xeroderma pigmentosum cells of complementation groups A and D following exposure to CC-1065. Since this NAD depletion is presumably associated with repair-induced incision, the repair of CC-1065-DNA adducts can probably take place by a pathway distinct from that involved in repair of more conventional bulky DNA adducts. The prolonged depletion of NAD, even at low doses of drug, suggests that CC-1065 causes DNA damage that results in a delay or block in DNA excision repair between the excision and ligation steps.

Original languageEnglish (US)
Pages (from-to)5929-5932
Number of pages4
JournalBiochemistry
Volume25
Issue number20
DOIs
StatePublished - Oct 1986
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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