Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the effect of inhibitors of ADP-ribosyltransferase on the cytotoxicity of a range of S-phase acting drugs. Co-administration of 3 mM 3-aminobenzamide (3AB) potentiated the cytotoxicity of TG 2-fold, but had no effect on the cytotoxicity of HU, FdUrd or araC. Higher concentrations of benzamides (e.g. 10-20 mM 3AB) produced a G1-specific cell cycle blockade. This treatment prevented cells entering S-phase DNA synthesis and consequently protected against the cytotoxicity of the same S-phase acting drugs. Thus, using different treatment regimens with 3AB, it was possible to either potentiate or protect against the cytotoxicity of TG.
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PMID:Adenosine-diphosphoribosyltransferase inhibitors can protect against or potentiate the cytotoxicity of S-phase acting drugs. 313 71

5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, and both agents undergo intracellular processing to active metabolites that disrupt RNA and DNA metabolism. These agents cause imbalances in deoxynucleotide triphosphate levels and the accumulation of uracil and 5-FU in the genome, events that activate the ATR- and ATM-dependent checkpoint signaling pathways and the base excision repair (BER) pathway. Here, we assessed which DNA damage response and repair processes influence 5-FU and FdUrd toxicity in ovarian cancer cells. These studies revealed that disabling the ATM, ATR, or BER pathways using small inhibitory RNAs did not affect 5-FU cytotoxicity. In stark contrast, ATR and a functional BER pathway protected FdUrd-treated cells. Consistent with a role for the BER pathway, the poly(ADP-ribose) polymerase (PARP) inhibitors ABT-888 (veliparib) and AZD2281 (olaparib) markedly synergized with FdUrd but not with 5-FU in ovarian cancer cell lines. Furthermore, ABT-888 synergized with FdUrd far more effectively than other agents commonly used to treat ovarian cancer. These findings underscore differences in the cytotoxic mechanisms of 5-FU and FdUrd and suggest that combining FdUrd and PARP inhibitors may be an innovative therapeutic strategy for ovarian tumors.
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PMID:Poly(ADP-Ribose) polymerase inhibition synergizes with 5-fluorodeoxyuridine but not 5-fluorouracil in ovarian cancer cells. 2161 6

The fluoropyrimidines 5-fluorouracil (5-FU) and FdUrd (5-fluorodeoxyuridine; floxuridine) are the backbone of chemotherapy regimens for colon cancer and other tumors. Despite their widespread use, it remains unclear how these agents kill tumor cells. Here, we have analyzed the checkpoint and DNA repair pathways that affect colon tumor responses to 5-FU and FdUrd. These studies demonstrate that both FdUrd and 5-FU activate the ATR and ATM checkpoint signaling pathways, indicating that they cause genotoxic damage. Notably, however, depletion of ATM or ATR does not sensitize colon cancer cells to 5-FU, whereas these checkpoint pathways promote the survival of cells treated with FdUrd, suggesting that FdUrd exerts cytotoxicity by disrupting DNA replication and/or inducing DNA damage, whereas 5-FU does not. We also found that disabling the base excision (BER) repair pathway by depleting XRCC1 or APE1 sensitized colon cancer cells to FdUrd but not 5-FU. Consistent with a role for the BER pathway, we show that small molecule poly(ADP-ribose) polymerase 1/2 (PARP) inhibitors, AZD2281 and ABT-888, remarkably sensitized both mismatch repair (MMR)-proficient and -deficient colon cancer cell lines to FdUrd but not to 5-FU. Taken together, these studies demonstrate that the roles of genotoxin-induced checkpoint signaling and DNA repair differ significantly for these agents and also suggest a novel approach to colon cancer therapy in which FdUrd is combined with a small molecule PARP inhibitor.
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PMID:Checkpoint signaling, base excision repair, and PARP promote survival of colon cancer cells treated with 5-fluorodeoxyuridine but not 5-fluorouracil. 2219 30

Floxuridine (5-fluorodeoxyuridine, FdUrd), a U.S. Food and Drug Administration-approved drug and metabolite of 5-fluorouracil, causes DNA damage that is repaired by base excision repair (BER). Thus, poly(ADP-ribose) polymerase (PARP) inhibitors, which disrupt BER, markedly sensitize ovarian cancer cells to FdUrd, suggesting that this combination may have activity in this disease. It remains unclear, however, which DNA repair and checkpoint signaling pathways affect killing by these agents individually and in combination. Here we show that depleting ATR, BRCA1, BRCA2, or RAD51 sensitized to ABT-888 (veliparib) alone, FdUrd alone, and FdUrd + ABT-888 (F+A), suggesting that homologous recombination (HR) repair protects cells exposed to these agents. In contrast, disabling the mismatch, nucleotide excision, Fanconi anemia, nonhomologous end joining, or translesion synthesis repair pathways did not sensitize to these agents alone (including ABT-888) or in combination. Further studies demonstrated that in BRCA1-depleted cells, F+A was more effective than other chemotherapy+ABT-888 combinations. Taken together, these studies 1) identify DNA repair and checkpoint pathways that are important in ovarian cancer cells treated with FdUrd, ABT-888, and F+A, 2) show that disabling HR at the level of ATR, BRCA1, BRCA2, or RAD51, but not Chk1, ATM, PTEN, or FANCD2, sensitizes cells to ABT-888, and 3) demonstrate that even though ABT-888 sensitizes ovarian tumor cells with functional HR to FdUrd, the effects of this drug combination are more profound in tumors with HR defects, even compared with other chemotherapy + ABT-888 combinations, including cisplatin + ABT-888.
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PMID:Identification of DNA repair pathways that affect the survival of ovarian cancer cells treated with a poly(ADP-ribose) polymerase inhibitor in a novel drug combination. 2283 73