DNA repair, ADP-ribosylation and pyridine nucleotide metabolism as targets for cancer chemotherapy.
DNA repair mechanisms serve as useful targets for modulating the cytotoxic and chemotherapeutic effects of many agents whose mechanism of action involves the induction of DNA damage. For example, the modified base O6-methylguanine can inactivate the repair protein O6-alkylguanine alkyltransferase, thereby sensitizing cells to the cytotoxic effects of clinically useful nitrosoureas such as BCNU. Some of the cytotoxic DNA adducts induced by BCNU are repaired by O6-alkylguanine alkyltransferase; thus, inactivation of the protein by O6-methylguanine converts cells that are relatively resistant to BCNU into sensitive cells. Another cellular enzyme, poly(ADP-ribose) polymerase, responds to DNA strand breaks by cleaving its substrate, NAD+, and using the resultant ADP-ribose moieties to synthesize homopolymers of ADP-ribose. The use of agents such as benzamide derivatives to inhibit enzyme function results in the accumulation of DNA strand breaks and potentiates the tumoricidal effects of some DNA strand-breaking agents such as bleomycin. Poly(ADP-ribose) polymerase can also affect pyridine nucleotide metabolism in a manner that initiates biochemical alterations leading directly to cell death. Thus, the amount of NAD used in the synthesis of poly(ADP-ribose) is dependent on the number of DNA strand breaks present in the cells. DNA damage can sufficiently activate the enzyme to rapidly consume NAD and consequently deplete ATP levels, resulting in the cessation of all energy-dependent functions and cell death. Understanding this biochemical pathway that leads to cell death provides a new basis for modulating chemotherapy. For example, agents such as Tiazofurin and/or 6-aminonicotinamide can each be used to alter pyridine nucleotide metabolism, lower NAD pools and potentiate the cytotoxic effects of other chemotherapeutic agents whose primary target is the induction of DNA damage.
Berger
N A
NA
Department of Medicine, Ireland Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
Berger
S J
SJ
Gerson
S L
SL
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects*; D008780:Methyltransferases / Q000502:physiology; D009243:NAD / Q000378:metabolism*; D009702:Nucleoside Diphosphate Sugars / Q000096:biosynthesis*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D009702:Nucleoside Diphosphate Sugars; D009243:NAD; D011064:Poly Adenosine Diphosphate Ribose; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine