Материалы доступны только для специалистов сферы здравоохранения.
Чтобы посмотреть материал полностью
Авторизуйтесь
или зарегистрируйтесь.
PARP-ингибиторы при новообразованиях женской репродуктивной системы
PARP-ингибиторы при новообразованиях женской репродуктивной системы
Покатаев И.А., Тюляндин С.А. PARP-ингибиторы при новообразованиях женской репродуктивной системы. Современная Онкология. 2017; 19 (2): 10–15.
________________________________________________
Материалы доступны только для специалистов сферы здравоохранения.
Чтобы посмотреть материал полностью
Авторизуйтесь
или зарегистрируйтесь.
Аннотация
Ферменты PARP-1 и PARP-2 участвуют в работе одной из шести известных систем репарации повреждений ДНК – эксцизионной репарации азотистых оснований. Ингибирование PARP нарушает работу эксцизионной репарации, что в условиях дефицита функции другого пути репарации ДНК – гомологичной рекомбинации – приводит к апоптозу опухолевых клеток. Одной из наиболее частых причин нарушения работы гомологичной рекомбинации является потеря функции белков BRCA1 или BRCA2 за счет инактивирующих мутаций, что делает группу PARP-ингибиторов наиболее эффективной именно при опухолях с герминальными или соматическими мутациями BRCA. В настоящей работе обсуждаются различия PARP-ингибиторов между собой (олапариба, нирапариба, велипариба, рукапариба и талазопариба), результаты их клинического изучения при опухолях женской репродуктивной системы, токсичность при применении этих препаратов в монорежиме и комбинации с цитотоксическими препаратами, а также данные о регистрации указанных препаратов в России и других странах.
Ключевые слова: олапариб, рак яичников, рак молочной железы, BRCA.
Key words: olaparib, ovarian cancer, breast cancer, BRCA.
Ключевые слова: олапариб, рак яичников, рак молочной железы, BRCA.
________________________________________________
Key words: olaparib, ovarian cancer, breast cancer, BRCA.
Полный текст
Список литературы
1. Cseh AM, Fábián Z, Sümegi B, Scorrano L. Poly(adenosine diphosphate-ribose) polymerase as therapeutic target: lessons learned from its inhibitors. Oncotarget 2017.
2. Herceg Z, Wang ZQ. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 2001; 422 (1–2): 97–110.
3. Liu Y, Prasad R, Beard WA et al. Coordination of Steps in Single-nucleotide Base Excision Repair Mediated by Apurinic/Apyrimidinic Endonuclease 1 and DNA Polymerase b. J Biol Chem 2007; 282 (18): 13532–41.
4. Amé JC, Rolli V, Schreiber V et al. PARP-2, A novelmammalian DNA damage dependent poly(ADP-ribose) polymerase. J Biol Chem 1999; 274: 17860–8.
5. Ba X, Garg NJ. Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol 2011; 178: 946–55.
6. Mortusewicz O, Amé JC, Schreiber V et al. Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells. Nucleic Acids Res 2007; 35 (22): 7665–75.
7. Okano S, Lan L, Caldecott KW et al. Spatial and temporal cellular responses to single-strand breaks in human cells. Mol Cell Biol 2003; 23 (11): 3974–81.
8. Schreiber V, Amé JC, Dollé P et al. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 2002; 277 (25): 23028–36.
9. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434: 917–21.
10. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian Carcinoma. Nature 2011; 474: 609615.
11. Chernikova S, Game J, Brown J. Inhibiting homologous recombination for cancer therapy. Cancer Biol Ther 2012; 13 (2): 61–8.
12. Dedes KJ, Wilkerson PM, Wetterskog D et al. Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. Cell Cycle 2011; 10 (8): 1192–9.
13. Murai J, Huang SN, Das BB et al. Differential trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 2012; 72 (21): 5588–99.
14. Pommier Y, O'Connor MJ, de Bono J et al. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med 2016; 8 (362): 362ps17.
15. Корман Д.Б. Основы противоопухолевой химиотерапии. М.: Практическая медицина, 2006. / Korman D.B. Osnovy protivoopukholevoi khimioterapii. M.: Prakticheskaia meditsina, 2006. [in Russian]
16. Murai J, Huang SN, Renaud A et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 2014; 13 (2): 433–43.
17. Krishnakumar R, Kraus WL. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell 2010; 39: 8–24.
18. Kaufman B, Shapira-Frommer R, Schmutzler R et al. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. J Clin Oncol 2015; 33 (3): 244250.
19. Покатаев И.А., Стенина М.Б., Чития Л.В. и др. Ретроспективный анализ эффективности химиотерапии при платинорезистентном и платинорефрактерном раке яичников. Вестн. РОНЦ. 2009; 20 (2): 34–40. / Pokataev I.A., Stenina M.B., Chitiia L.V. i dr. Retrospektivnyi analiz effektivnosti khimioterapii pri platinorezistentnom i platinorefrakternom rake iaichnikov. Vestn. RONTs. 2009; 20 (2): 34–40. [in Russian]
20. Committee for Medicinal Products for Human Use. Lynparza (olaparib). 23 October 2014. EMA/CHMP/632090/2014. http://www. ema.europa. eu/ema/ index.jsp?curl =pages/medicines/human/medicines/003726/ smops/ Positive/human_smop_ 000744.jsp&mid= WC0b01ac058001d127
21. Ledermann J, Harter P, Gourley C et al. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. N Engl J Med 2012; 366: 1382–92.
22. Ledermann J, Harter P, Gourley C et al. Overall survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: An interim analysis. J Clin Oncol 2016; 34 (Suppl.; abstr 5501).
23. Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinumsensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15 (8): 852–61.
24. Pujade-Lauraine E, Ledermann JA, Penson RT et al; Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in patients with platinum-sensitive relapsed ovarian cancer: Results from the phase III SOLO2 study. 2017 Society of Gynecologic Oncologists Annual Meeting. Abstract LBA2. Presented March 14, 2017.
25. Robson M, Seock-Ah Im, Senkus E et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017.
26. Shen Y, Aoyagi-Scharber M, Wang B. Trapping poly(ADP-ribose) polymerase. J Pharmacol Exp Ther 2015; 353: 446–57.
27. Rugo HS, Olopade OI, DeMichele A et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 2016; 375: 23–34.
28. Geyer CE, O'Shaughnessy J, Untch M et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). J Clin Oncol 2017; 35 (Suppl.; abstr 520).
29. Mirza MR, Monk BJ, Herrstedt J et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; 375 (22): 2154–64.
30. Wahlberg E, Karlberg T, Kouznetsova E et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol 2012; 30: 283–8.
31. Shapira-Frommer R, Oza AM, Domchek SM et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment ofpatients with relapsed ovarian cancer and a deleterious BRCA mutation. J Clin Oncol 2015; 33 (Suppl.; abstr 5513).
32. González Martin A. Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer? Lancet Oncol 2016. Swisher EM, Lin KK, Oza AM, Scott CLet al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2016.
33. US Food and Drug Administration (FDA). FDA grants accelerated approval to new treatment for advanced ovarian cancer (media release). 2016.
34. De Bono JS, Mina LA, Gonzalez M et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. In: ASCO Annual Meeting Proceedings, 2013.
35. Jenner ZB, Sood AK, Coleman RL. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol 2016; 12: 1439–5648, 61.
36. De Bono J, Ramanathan RK, Mina L et al. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov 2017; 7 (6): 620–9.
37. Turner NC, Telli ML, Rugo HS et al. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO). J Clin Oncol 2017; 35 (Suppl.; abstr 1007).
38. Kaye SB, Lubinski J, Matulonis U et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADPribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 2012; 30: 372–9.
39. Bixel K, Hays JL. Olaparib in the management of ovarian cancer. Pharmgenomics Pers Med 2015; 8: 127–35.
40. Ricks TK, Chiu HJ, Ison G et al. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol 2015; 5: 222.
41. Puhalla S, Beumer JH, Pahuja S et al. Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either BRCA1/2-mutated cancer (BRCA+), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt). In: ASCO Annual Meeting Proceedings, 2014.
42. Coleman RL, Sill MW, Bell-McGuinn K et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation – an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 2015; 137: 386–91.
43. Kummar S, Kinders R, Gutierrez ME et al. Phase 0 clinical trial of the poly (ADPribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 2009; 27: 2705–11.
44. Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18 (1): 75–87.
45. Lin K, Sun J, Maloney L et al. 2701 quantification of genomic loss of heterozygosity enables prospective selection of ovarian cancer patients who may derive benefit from the PARP inhibitor rucaparib. Eur J Cancer 2015; 51: S531–2.
46. Sun JX, Frampton G, Wang K et al. A computational method for somatic versus germline variant status determination from targeted next-generation sequencing of clinical cancer specimens without a matched normal control. Cancer Res 2014; 74: 1893.
47. Coleman RL, Swisher EM, Oza AM et al. Refinement of prespecified cutoff for genomic loss of heterozygosity (LOH) in ARIEL2 part 1: a phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC). In: ASCO Annual Meeting Proceedings, 2016.
48. Swisher EM, McNeish IA, Coleman RL et al. ARIEL 2/3: an integrated clinical trial program to assess activity of rucaparib in ovarian cancer and to identify tumor molecular characteristics predictive of response. In: ASCO Annual Meeting Proceedings, 2014
49. Telli ML, Jensen KC, Vinayak S et al. Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumorbased measure of genomic instability: PrECOG 0105. J Clin Oncol 2015; 33: 1895–901.
50. Abkevich V, Timms KM, Hennessy BT et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012; 107: 1776–82.
2. Herceg Z, Wang ZQ. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 2001; 422 (1–2): 97–110.
3. Liu Y, Prasad R, Beard WA et al. Coordination of Steps in Single-nucleotide Base Excision Repair Mediated by Apurinic/Apyrimidinic Endonuclease 1 and DNA Polymerase b. J Biol Chem 2007; 282 (18): 13532–41.
4. Amé JC, Rolli V, Schreiber V et al. PARP-2, A novelmammalian DNA damage dependent poly(ADP-ribose) polymerase. J Biol Chem 1999; 274: 17860–8.
5. Ba X, Garg NJ. Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol 2011; 178: 946–55.
6. Mortusewicz O, Amé JC, Schreiber V et al. Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells. Nucleic Acids Res 2007; 35 (22): 7665–75.
7. Okano S, Lan L, Caldecott KW et al. Spatial and temporal cellular responses to single-strand breaks in human cells. Mol Cell Biol 2003; 23 (11): 3974–81.
8. Schreiber V, Amé JC, Dollé P et al. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 2002; 277 (25): 23028–36.
9. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434: 917–21.
10. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian Carcinoma. Nature 2011; 474: 609615.
11. Chernikova S, Game J, Brown J. Inhibiting homologous recombination for cancer therapy. Cancer Biol Ther 2012; 13 (2): 61–8.
12. Dedes KJ, Wilkerson PM, Wetterskog D et al. Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. Cell Cycle 2011; 10 (8): 1192–9.
13. Murai J, Huang SN, Das BB et al. Differential trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 2012; 72 (21): 5588–99.
14. Pommier Y, O'Connor MJ, de Bono J et al. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med 2016; 8 (362): 362ps17.
15. Korman D.B. Osnovy protivoopukholevoi khimioterapii. M.: Prakticheskaia meditsina, 2006. [in Russian]
16. Murai J, Huang SN, Renaud A et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 2014; 13 (2): 433–43.
17. Krishnakumar R, Kraus WL. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell 2010; 39: 8–24.
18. Kaufman B, Shapira-Frommer R, Schmutzler R et al. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. J Clin Oncol 2015; 33 (3): 244250.
19. Pokataev I.A., Stenina M.B., Chitiia L.V. i dr. Retrospektivnyi analiz effektivnosti khimioterapii pri platinorezistentnom i platinorefrakternom rake iaichnikov. Vestn. RONTs. 2009; 20 (2): 34–40. [in Russian]
20. Committee for Medicinal Products for Human Use. Lynparza (olaparib). 23 October 2014. EMA/CHMP/632090/2014. http://www. ema.europa. eu/ema/ index.jsp?curl =pages/medicines/human/medicines/003726/ smops/ Positive/human_smop_ 000744.jsp&mid= WC0b01ac058001d127
21. Ledermann J, Harter P, Gourley C et al. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. N Engl J Med 2012; 366: 1382–92.
22. Ledermann J, Harter P, Gourley C et al. Overall survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: An interim analysis. J Clin Oncol 2016; 34 (Suppl.; abstr 5501).
23. Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinumsensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15 (8): 852–61.
24. Pujade-Lauraine E, Ledermann JA, Penson RT et al; Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in patients with platinum-sensitive relapsed ovarian cancer: Results from the phase III SOLO2 study. 2017 Society of Gynecologic Oncologists Annual Meeting. Abstract LBA2. Presented March 14, 2017.
25. Robson M, Seock-Ah Im, Senkus E et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017.
26. Shen Y, Aoyagi-Scharber M, Wang B. Trapping poly(ADP-ribose) polymerase. J Pharmacol Exp Ther 2015; 353: 446–57.
27. Rugo HS, Olopade OI, DeMichele A et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 2016; 375: 23–34.
28. Geyer CE, O'Shaughnessy J, Untch M et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). J Clin Oncol 2017; 35 (Suppl.; abstr 520).
29. Mirza MR, Monk BJ, Herrstedt J et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; 375 (22): 2154–64.
30. Wahlberg E, Karlberg T, Kouznetsova E et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol 2012; 30: 283–8.
31. Shapira-Frommer R, Oza AM, Domchek SM et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment ofpatients with relapsed ovarian cancer and a deleterious BRCA mutation. J Clin Oncol 2015; 33 (Suppl.; abstr 5513).
32. González Martin A. Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer? Lancet Oncol 2016. Swisher EM, Lin KK, Oza AM, Scott CLet al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2016.
33. US Food and Drug Administration (FDA). FDA grants accelerated approval to new treatment for advanced ovarian cancer (media release). 2016.
34. De Bono JS, Mina LA, Gonzalez M et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. In: ASCO Annual Meeting Proceedings, 2013.
35. Jenner ZB, Sood AK, Coleman RL. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol 2016; 12: 1439–5648, 61.
36. De Bono J, Ramanathan RK, Mina L et al. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov 2017; 7 (6): 620–9.
37. Turner NC, Telli ML, Rugo HS et al. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO). J Clin Oncol 2017; 35 (Suppl.; abstr 1007).
38. Kaye SB, Lubinski J, Matulonis U et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADPribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 2012; 30: 372–9.
39. Bixel K, Hays JL. Olaparib in the management of ovarian cancer. Pharmgenomics Pers Med 2015; 8: 127–35.
40. Ricks TK, Chiu HJ, Ison G et al. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol 2015; 5: 222.
41. Puhalla S, Beumer JH, Pahuja S et al. Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either BRCA1/2-mutated cancer (BRCA+), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt). In: ASCO Annual Meeting Proceedings, 2014.
42. Coleman RL, Sill MW, Bell-McGuinn K et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation – an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 2015; 137: 386–91.
43. Kummar S, Kinders R, Gutierrez ME et al. Phase 0 clinical trial of the poly (ADPribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 2009; 27: 2705–11.
44. Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18 (1): 75–87.
45. Lin K, Sun J, Maloney L et al. 2701 quantification of genomic loss of heterozygosity enables prospective selection of ovarian cancer patients who may derive benefit from the PARP inhibitor rucaparib. Eur J Cancer 2015; 51: S531–2.
46. Sun JX, Frampton G, Wang K et al. A computational method for somatic versus germline variant status determination from targeted next-generation sequencing of clinical cancer specimens without a matched normal control. Cancer Res 2014; 74: 1893.
47. Coleman RL, Swisher EM, Oza AM et al. Refinement of prespecified cutoff for genomic loss of heterozygosity (LOH) in ARIEL2 part 1: a phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC). In: ASCO Annual Meeting Proceedings, 2016.
48. Swisher EM, McNeish IA, Coleman RL et al. ARIEL 2/3: an integrated clinical trial program to assess activity of rucaparib in ovarian cancer and to identify tumor molecular characteristics predictive of response. In: ASCO Annual Meeting Proceedings, 2014
49. Telli ML, Jensen KC, Vinayak S et al. Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumorbased measure of genomic instability: PrECOG 0105. J Clin Oncol 2015; 33: 1895–901.
50. Abkevich V, Timms KM, Hennessy BT et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012; 107: 1776–82.
2. Herceg Z, Wang ZQ. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 2001; 422 (1–2): 97–110.
3. Liu Y, Prasad R, Beard WA et al. Coordination of Steps in Single-nucleotide Base Excision Repair Mediated by Apurinic/Apyrimidinic Endonuclease 1 and DNA Polymerase b. J Biol Chem 2007; 282 (18): 13532–41.
4. Amé JC, Rolli V, Schreiber V et al. PARP-2, A novelmammalian DNA damage dependent poly(ADP-ribose) polymerase. J Biol Chem 1999; 274: 17860–8.
5. Ba X, Garg NJ. Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol 2011; 178: 946–55.
6. Mortusewicz O, Amé JC, Schreiber V et al. Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells. Nucleic Acids Res 2007; 35 (22): 7665–75.
7. Okano S, Lan L, Caldecott KW et al. Spatial and temporal cellular responses to single-strand breaks in human cells. Mol Cell Biol 2003; 23 (11): 3974–81.
8. Schreiber V, Amé JC, Dollé P et al. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 2002; 277 (25): 23028–36.
9. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434: 917–21.
10. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian Carcinoma. Nature 2011; 474: 609615.
11. Chernikova S, Game J, Brown J. Inhibiting homologous recombination for cancer therapy. Cancer Biol Ther 2012; 13 (2): 61–8.
12. Dedes KJ, Wilkerson PM, Wetterskog D et al. Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. Cell Cycle 2011; 10 (8): 1192–9.
13. Murai J, Huang SN, Das BB et al. Differential trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 2012; 72 (21): 5588–99.
14. Pommier Y, O'Connor MJ, de Bono J et al. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med 2016; 8 (362): 362ps17.
15. Корман Д.Б. Основы противоопухолевой химиотерапии. М.: Практическая медицина, 2006. / Korman D.B. Osnovy protivoopukholevoi khimioterapii. M.: Prakticheskaia meditsina, 2006. [in Russian]
16. Murai J, Huang SN, Renaud A et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 2014; 13 (2): 433–43.
17. Krishnakumar R, Kraus WL. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell 2010; 39: 8–24.
18. Kaufman B, Shapira-Frommer R, Schmutzler R et al. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. J Clin Oncol 2015; 33 (3): 244250.
19. Покатаев И.А., Стенина М.Б., Чития Л.В. и др. Ретроспективный анализ эффективности химиотерапии при платинорезистентном и платинорефрактерном раке яичников. Вестн. РОНЦ. 2009; 20 (2): 34–40. / Pokataev I.A., Stenina M.B., Chitiia L.V. i dr. Retrospektivnyi analiz effektivnosti khimioterapii pri platinorezistentnom i platinorefrakternom rake iaichnikov. Vestn. RONTs. 2009; 20 (2): 34–40. [in Russian]
20. Committee for Medicinal Products for Human Use. Lynparza (olaparib). 23 October 2014. EMA/CHMP/632090/2014. http://www. ema.europa. eu/ema/ index.jsp?curl =pages/medicines/human/medicines/003726/ smops/ Positive/human_smop_ 000744.jsp&mid= WC0b01ac058001d127
21. Ledermann J, Harter P, Gourley C et al. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. N Engl J Med 2012; 366: 1382–92.
22. Ledermann J, Harter P, Gourley C et al. Overall survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: An interim analysis. J Clin Oncol 2016; 34 (Suppl.; abstr 5501).
23. Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinumsensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15 (8): 852–61.
24. Pujade-Lauraine E, Ledermann JA, Penson RT et al; Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in patients with platinum-sensitive relapsed ovarian cancer: Results from the phase III SOLO2 study. 2017 Society of Gynecologic Oncologists Annual Meeting. Abstract LBA2. Presented March 14, 2017.
25. Robson M, Seock-Ah Im, Senkus E et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017.
26. Shen Y, Aoyagi-Scharber M, Wang B. Trapping poly(ADP-ribose) polymerase. J Pharmacol Exp Ther 2015; 353: 446–57.
27. Rugo HS, Olopade OI, DeMichele A et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 2016; 375: 23–34.
28. Geyer CE, O'Shaughnessy J, Untch M et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). J Clin Oncol 2017; 35 (Suppl.; abstr 520).
29. Mirza MR, Monk BJ, Herrstedt J et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; 375 (22): 2154–64.
30. Wahlberg E, Karlberg T, Kouznetsova E et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol 2012; 30: 283–8.
31. Shapira-Frommer R, Oza AM, Domchek SM et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment ofpatients with relapsed ovarian cancer and a deleterious BRCA mutation. J Clin Oncol 2015; 33 (Suppl.; abstr 5513).
32. González Martin A. Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer? Lancet Oncol 2016. Swisher EM, Lin KK, Oza AM, Scott CLet al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2016.
33. US Food and Drug Administration (FDA). FDA grants accelerated approval to new treatment for advanced ovarian cancer (media release). 2016.
34. De Bono JS, Mina LA, Gonzalez M et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. In: ASCO Annual Meeting Proceedings, 2013.
35. Jenner ZB, Sood AK, Coleman RL. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol 2016; 12: 1439–5648, 61.
36. De Bono J, Ramanathan RK, Mina L et al. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov 2017; 7 (6): 620–9.
37. Turner NC, Telli ML, Rugo HS et al. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO). J Clin Oncol 2017; 35 (Suppl.; abstr 1007).
38. Kaye SB, Lubinski J, Matulonis U et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADPribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 2012; 30: 372–9.
39. Bixel K, Hays JL. Olaparib in the management of ovarian cancer. Pharmgenomics Pers Med 2015; 8: 127–35.
40. Ricks TK, Chiu HJ, Ison G et al. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol 2015; 5: 222.
41. Puhalla S, Beumer JH, Pahuja S et al. Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either BRCA1/2-mutated cancer (BRCA+), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt). In: ASCO Annual Meeting Proceedings, 2014.
42. Coleman RL, Sill MW, Bell-McGuinn K et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation – an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 2015; 137: 386–91.
43. Kummar S, Kinders R, Gutierrez ME et al. Phase 0 clinical trial of the poly (ADPribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 2009; 27: 2705–11.
44. Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18 (1): 75–87.
45. Lin K, Sun J, Maloney L et al. 2701 quantification of genomic loss of heterozygosity enables prospective selection of ovarian cancer patients who may derive benefit from the PARP inhibitor rucaparib. Eur J Cancer 2015; 51: S531–2.
46. Sun JX, Frampton G, Wang K et al. A computational method for somatic versus germline variant status determination from targeted next-generation sequencing of clinical cancer specimens without a matched normal control. Cancer Res 2014; 74: 1893.
47. Coleman RL, Swisher EM, Oza AM et al. Refinement of prespecified cutoff for genomic loss of heterozygosity (LOH) in ARIEL2 part 1: a phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC). In: ASCO Annual Meeting Proceedings, 2016.
48. Swisher EM, McNeish IA, Coleman RL et al. ARIEL 2/3: an integrated clinical trial program to assess activity of rucaparib in ovarian cancer and to identify tumor molecular characteristics predictive of response. In: ASCO Annual Meeting Proceedings, 2014
49. Telli ML, Jensen KC, Vinayak S et al. Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumorbased measure of genomic instability: PrECOG 0105. J Clin Oncol 2015; 33: 1895–901.
50. Abkevich V, Timms KM, Hennessy BT et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012; 107: 1776–82.
________________________________________________
2. Herceg Z, Wang ZQ. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 2001; 422 (1–2): 97–110.
3. Liu Y, Prasad R, Beard WA et al. Coordination of Steps in Single-nucleotide Base Excision Repair Mediated by Apurinic/Apyrimidinic Endonuclease 1 and DNA Polymerase b. J Biol Chem 2007; 282 (18): 13532–41.
4. Amé JC, Rolli V, Schreiber V et al. PARP-2, A novelmammalian DNA damage dependent poly(ADP-ribose) polymerase. J Biol Chem 1999; 274: 17860–8.
5. Ba X, Garg NJ. Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol 2011; 178: 946–55.
6. Mortusewicz O, Amé JC, Schreiber V et al. Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells. Nucleic Acids Res 2007; 35 (22): 7665–75.
7. Okano S, Lan L, Caldecott KW et al. Spatial and temporal cellular responses to single-strand breaks in human cells. Mol Cell Biol 2003; 23 (11): 3974–81.
8. Schreiber V, Amé JC, Dollé P et al. Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 2002; 277 (25): 23028–36.
9. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434: 917–21.
10. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian Carcinoma. Nature 2011; 474: 609615.
11. Chernikova S, Game J, Brown J. Inhibiting homologous recombination for cancer therapy. Cancer Biol Ther 2012; 13 (2): 61–8.
12. Dedes KJ, Wilkerson PM, Wetterskog D et al. Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations. Cell Cycle 2011; 10 (8): 1192–9.
13. Murai J, Huang SN, Das BB et al. Differential trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 2012; 72 (21): 5588–99.
14. Pommier Y, O'Connor MJ, de Bono J et al. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci Transl Med 2016; 8 (362): 362ps17.
15. Korman D.B. Osnovy protivoopukholevoi khimioterapii. M.: Prakticheskaia meditsina, 2006. [in Russian]
16. Murai J, Huang SN, Renaud A et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 2014; 13 (2): 433–43.
17. Krishnakumar R, Kraus WL. The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol Cell 2010; 39: 8–24.
18. Kaufman B, Shapira-Frommer R, Schmutzler R et al. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. J Clin Oncol 2015; 33 (3): 244250.
19. Pokataev I.A., Stenina M.B., Chitiia L.V. i dr. Retrospektivnyi analiz effektivnosti khimioterapii pri platinorezistentnom i platinorefrakternom rake iaichnikov. Vestn. RONTs. 2009; 20 (2): 34–40. [in Russian]
20. Committee for Medicinal Products for Human Use. Lynparza (olaparib). 23 October 2014. EMA/CHMP/632090/2014. http://www. ema.europa. eu/ema/ index.jsp?curl =pages/medicines/human/medicines/003726/ smops/ Positive/human_smop_ 000744.jsp&mid= WC0b01ac058001d127
21. Ledermann J, Harter P, Gourley C et al. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. N Engl J Med 2012; 366: 1382–92.
22. Ledermann J, Harter P, Gourley C et al. Overall survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: An interim analysis. J Clin Oncol 2016; 34 (Suppl.; abstr 5501).
23. Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinumsensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15 (8): 852–61.
24. Pujade-Lauraine E, Ledermann JA, Penson RT et al; Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in patients with platinum-sensitive relapsed ovarian cancer: Results from the phase III SOLO2 study. 2017 Society of Gynecologic Oncologists Annual Meeting. Abstract LBA2. Presented March 14, 2017.
25. Robson M, Seock-Ah Im, Senkus E et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017.
26. Shen Y, Aoyagi-Scharber M, Wang B. Trapping poly(ADP-ribose) polymerase. J Pharmacol Exp Ther 2015; 353: 446–57.
27. Rugo HS, Olopade OI, DeMichele A et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 2016; 375: 23–34.
28. Geyer CE, O'Shaughnessy J, Untch M et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). J Clin Oncol 2017; 35 (Suppl.; abstr 520).
29. Mirza MR, Monk BJ, Herrstedt J et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; 375 (22): 2154–64.
30. Wahlberg E, Karlberg T, Kouznetsova E et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat Biotechnol 2012; 30: 283–8.
31. Shapira-Frommer R, Oza AM, Domchek SM et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment ofpatients with relapsed ovarian cancer and a deleterious BRCA mutation. J Clin Oncol 2015; 33 (Suppl.; abstr 5513).
32. González Martin A. Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer? Lancet Oncol 2016. Swisher EM, Lin KK, Oza AM, Scott CLet al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2016.
33. US Food and Drug Administration (FDA). FDA grants accelerated approval to new treatment for advanced ovarian cancer (media release). 2016.
34. De Bono JS, Mina LA, Gonzalez M et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. In: ASCO Annual Meeting Proceedings, 2013.
35. Jenner ZB, Sood AK, Coleman RL. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol 2016; 12: 1439–5648, 61.
36. De Bono J, Ramanathan RK, Mina L et al. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discov 2017; 7 (6): 620–9.
37. Turner NC, Telli ML, Rugo HS et al. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO). J Clin Oncol 2017; 35 (Suppl.; abstr 1007).
38. Kaye SB, Lubinski J, Matulonis U et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADPribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 2012; 30: 372–9.
39. Bixel K, Hays JL. Olaparib in the management of ovarian cancer. Pharmgenomics Pers Med 2015; 8: 127–35.
40. Ricks TK, Chiu HJ, Ison G et al. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol 2015; 5: 222.
41. Puhalla S, Beumer JH, Pahuja S et al. Final results of a phase 1 study of single-agent veliparib (V) in patients (pts) with either BRCA1/2-mutated cancer (BRCA+), platinum-refractory ovarian, or basal-like breast cancer (BRCA-wt). In: ASCO Annual Meeting Proceedings, 2014.
42. Coleman RL, Sill MW, Bell-McGuinn K et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation – an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 2015; 137: 386–91.
43. Kummar S, Kinders R, Gutierrez ME et al. Phase 0 clinical trial of the poly (ADPribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 2009; 27: 2705–11.
44. Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18 (1): 75–87.
45. Lin K, Sun J, Maloney L et al. 2701 quantification of genomic loss of heterozygosity enables prospective selection of ovarian cancer patients who may derive benefit from the PARP inhibitor rucaparib. Eur J Cancer 2015; 51: S531–2.
46. Sun JX, Frampton G, Wang K et al. A computational method for somatic versus germline variant status determination from targeted next-generation sequencing of clinical cancer specimens without a matched normal control. Cancer Res 2014; 74: 1893.
47. Coleman RL, Swisher EM, Oza AM et al. Refinement of prespecified cutoff for genomic loss of heterozygosity (LOH) in ARIEL2 part 1: a phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC). In: ASCO Annual Meeting Proceedings, 2016.
48. Swisher EM, McNeish IA, Coleman RL et al. ARIEL 2/3: an integrated clinical trial program to assess activity of rucaparib in ovarian cancer and to identify tumor molecular characteristics predictive of response. In: ASCO Annual Meeting Proceedings, 2014
49. Telli ML, Jensen KC, Vinayak S et al. Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumorbased measure of genomic instability: PrECOG 0105. J Clin Oncol 2015; 33: 1895–901.
50. Abkevich V, Timms KM, Hennessy BT et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012; 107: 1776–82.
Авторы
И.А.Покатаев*, С.А.Тюляндин
ФГБУ «Российский онкологический научный центр им. Н.Н.Блохина» Минздрава России. 115478, Россия, Москва, Каширское ш., д. 23
*pokia@mail.ru
N.N.Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation. 115478, Russian Federation, Moscow, Kashirskoe sh., d. 23
*pokia@mail.ru
ФГБУ «Российский онкологический научный центр им. Н.Н.Блохина» Минздрава России. 115478, Россия, Москва, Каширское ш., д. 23
*pokia@mail.ru
________________________________________________
N.N.Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation. 115478, Russian Federation, Moscow, Kashirskoe sh., d. 23
*pokia@mail.ru
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.