Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors
| Autor: | Anna L. Olsen, Richard H. Wilson, Chris Jones, Patrick Johnson, Heidi Steinfeldt, Ruth Plummer, Mark R. Middleton, Hilary Calvert, Alan V. Boddy, Diane Wang, R. Dewji, L Robson, Nicola J. Curtin, Peter J. McHugh, Jeff Evans, David R. Newell, Adrian L. Harris |
|---|---|
| Přispěvatelé: | Plummer, Ruth, Jones, Christopher, Middleton, Mark, Wilson, Richard, Evans, Jeffrey, Olsen, Anna, Curtin, Nicola, Boddy, Alan, McHugh, Peter, Newell, David, Harris, Adrian, Johnson, Patrick, Steinfeldt, Heidi, Dewji, Raz, Wang, Diane, Robson, Lesley, Calvert, Hilary |
| Rok vydání: | 2008 |
| Předmět: |
Adult
Male Cancer Research Indoles medicine.medical_treatment Dacarbazine Poly ADP ribose polymerase Pharmacology Poly (ADP-Ribose) Polymerase Inhibitor Article chemistry.chemical_compound Pharmacokinetics Neoplasms Antineoplastic Combined Chemotherapy Protocols Temozolomide Medicine Humans Rucaparib Aged Chemotherapy business.industry DNA Breaks Middle Aged Oncology chemistry Cytochrome P-450 CYP2D6 Immunology PARP inhibitor Female Comet Assay business medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 14(23) |
| ISSN: | 1078-0432 |
| Popis: | Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|