Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase : a contributory factor to chemopotentiation in vivo?
PURPOSE: Poly(ADP-ribose) polymerase (PARP) plays an important role in DNA repair, and PARP inhibitors can enhance the activity of DNA-damaging agents in vitro and in vivo. AG014699 is a potent PARP inhibitor in phase II clinical development. However, the range of therapeutics with which AG014699 could interact via a DNA-repair based mechanism is limited. We aimed to investigate a novel, vascular-based activity of AG014699, underlying in vivo chemosensitization, which could widen its clinical application.
EXPERIMENTAL DESIGN: Temozolomide response was analyzed in vitro and in vivo. Vessel dynamics were monitored using "mismatch" following the administration of perfusion markers and real-time analysis of fluorescently labeled albumin uptake in to tumors established in dorsal window chambers. Further mechanistic investigations used ex vivo assays of vascular smooth muscle relaxation, gut motility, and myosin light chain kinase (MLCK) inhibition.
RESULTS: AG014699 failed to sensitize SW620 cells to temozolomide in vitro but induced pronounced enhancement in vivo. AG014699 (1 mg/kg) improved tumor perfusion comparably with the control agents nicotinamide (1 g/kg) and AG14361 (forerunner to AG014699; 10 mg/kg). AG014699 and AG14361 relaxed preconstricted vascular smooth muscle more potently than the standard agent, hydralazine, with no impact on gut motility. AG014699 inhibited MLCK at concentrations that relaxed isolated arteries, whereas AG14361 had no effect.
CONCLUSION: Increased vessel perfusion elicited by AG014699 could increase tumor drug accumulation and therapeutic response. Vasoactive concentrations of AG014699 do not cause detrimental side effects to gut motility and may increase the range of therapeutics with which AG014699 could be combined with for clinical benefit.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2009 |
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| Erschienen: |
2009 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 15(2009), 19 vom: 01. Okt., Seite 6106-12 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ali, Majid [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.12.2009 Date Revised 28.10.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-09-0398 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM191688134 |
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| 100 | 1 | |a Ali, Majid |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase |b a contributory factor to chemopotentiation in vivo? |
| 264 | 1 | |c 2009 | |
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| 500 | |a Date Completed 22.12.2009 | ||
| 500 | |a Date Revised 28.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: Poly(ADP-ribose) polymerase (PARP) plays an important role in DNA repair, and PARP inhibitors can enhance the activity of DNA-damaging agents in vitro and in vivo. AG014699 is a potent PARP inhibitor in phase II clinical development. However, the range of therapeutics with which AG014699 could interact via a DNA-repair based mechanism is limited. We aimed to investigate a novel, vascular-based activity of AG014699, underlying in vivo chemosensitization, which could widen its clinical application | ||
| 520 | |a EXPERIMENTAL DESIGN: Temozolomide response was analyzed in vitro and in vivo. Vessel dynamics were monitored using "mismatch" following the administration of perfusion markers and real-time analysis of fluorescently labeled albumin uptake in to tumors established in dorsal window chambers. Further mechanistic investigations used ex vivo assays of vascular smooth muscle relaxation, gut motility, and myosin light chain kinase (MLCK) inhibition | ||
| 520 | |a RESULTS: AG014699 failed to sensitize SW620 cells to temozolomide in vitro but induced pronounced enhancement in vivo. AG014699 (1 mg/kg) improved tumor perfusion comparably with the control agents nicotinamide (1 g/kg) and AG14361 (forerunner to AG014699; 10 mg/kg). AG014699 and AG14361 relaxed preconstricted vascular smooth muscle more potently than the standard agent, hydralazine, with no impact on gut motility. AG014699 inhibited MLCK at concentrations that relaxed isolated arteries, whereas AG14361 had no effect | ||
| 520 | |a CONCLUSION: Increased vessel perfusion elicited by AG014699 could increase tumor drug accumulation and therapeutic response. Vasoactive concentrations of AG014699 do not cause detrimental side effects to gut motility and may increase the range of therapeutics with which AG014699 could be combined with for clinical benefit | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 700 | 1 | |a O'Rourke, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Huw D |e verfasserin |4 aut | |
| 700 | 1 | |a Kamjoo, Marzieh |e verfasserin |4 aut | |
| 700 | 1 | |a Kyle, Suzanne |e verfasserin |4 aut | |
| 700 | 1 | |a Robson, Tracy |e verfasserin |4 aut | |
| 700 | 1 | |a Shaw, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Hirst, David G |e verfasserin |4 aut | |
| 700 | 1 | |a Curtin, Nicola J |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Kaye J |e verfasserin |4 aut | |
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