臨床婦人科産科65巻7号

2011年07月発行

今月の臨床 卵巣がん─最新の治療戦略

分子標的治療薬の種類と作用機序

著者： 島田宗昭¹ 板持広明¹ 紀川純三²

所属機関： ¹鳥取大学医学部産科婦人科 ²鳥取大学医学部附属病院がんセンター

ページ範囲：P.946 - P.953

　最近の分子生物学の進歩に伴い，がん細胞に特有の質的あるいは量的変化を有する分子を標的とする分子標的治療薬が開発されてきた．その標的は，血管新生・増殖因子およびその受容体，シグナル伝達系，DNA修復，転写制御因子など多岐にわたる．また，分子標的治療薬はその作用機序から抗体医薬（大分子化合物）とチロシンキナーゼ阻害薬などの小（低）分子化合物に大別される．すでに，肺癌や大腸癌などではいくつかの分子標的治療薬が保険収載され広く用いられている．一方，婦人科領域では臨床的に使用できる薬剤はなく，卵巣癌を主体に臨床試験が行われている現状にある．

　本稿では卵巣癌に対して臨床応用が試みられている分子標的治療薬の種類と作用機序に関して概説する．

参考文献

1） 板持広明，大石徹郎，紀川純三 : 婦人科がんのMolecular Biology 13．分子標的治療 産と婦108 : 108─114, 2011

2） Cannistra SA, Matulonis UA, Penson RT, et al : Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25 : 5180─5186, 2007

3） Burger RA, Sill MW, Monk BJ, et al : Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer : a Gynecologic Oncology Group Study. J Clin Oncol 25 : 5165─5171, 2007

4） Burger RA, Brady MF, Bookman MA, et al : Phase III trial of bevacizumab（BEV）in the primary treatment of advanced epithelial ovarian cancer（EOC）, primary peritoneal cancer（PPC）, or fallopian tube cancer（FTC） : A Gynecologic Oncology Group Study. Proc Am Soc Clin Oncol 28 : 5s LBA1, 2010

5） Tew WP, Colombo N, Ray-Coquard I, et al : VEGF Trap for patients with recurrent platinum-resistant epithelial ovarian cancer（EOC） : Preliminary results of randomized, multicenter phase II study. Proc Am Soc Clin Oncol 25 : 276s #5508, 2007

6） Friedlander M, Hancock KC, Rischin DA, et al : Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol 119 : 32─37, 2010

7） Matulonis UA, Berlin S, Ivy P, et al : Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 27 : 5601─5606, 2009

8） Matei D, Sill MW, Lankes HA, et al : Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis : a gynecologic oncology group trial. J Clin Oncol 29 : 69─75, 2011

9） Laird AD, Vajkoczy P, Shawver LK, et al : SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 60 : 4152─4160, 2000

10） Biagi JJ, Oza AM, Grimshaw R, et al : A phase II study of sunitinib（SU11248）in patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma-NCIC CTG IND 185. Proc Am Soc Clin Oncol 26 : 298s #5522, 2008

11） Schilder RJ, Sill MW, Lee RB, et al : Phase II evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma : a Gynecologic Oncology Group Study. J Clin Oncol 10 : 3418─3425, 2008

12） Lynch TJ, Bell DW, Sordella R, et al : Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 20 : 2129─2139, 2004

13） Sirotnak FM, Zakowski MF, Miller VA, et al : Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839（Iressa）, an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 6 : 4885─4892, 2000

14） Schilder RJ, Sill MW, Chen X, et al : Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression : a Gynecologic Oncology Group Study. Clin Cancer Res 11 : 5539─5548, 2005

15） Gordon AN, Finkler N, Edwards RP, et al : Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor（HER1／EGFR） tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma : results from a phase II multicenter study. Int J Gynecol Cancer 15 : 785─792, 2005

16） Peréz-Soler R, Saltz L : Cutaneous adverse effects with HER1／EGFR-targeted agents : is there a silver lining? J Clin Oncol 23 : 5235─5246, 2005

17） Secord AA, Blessing JA, Armstrong DK, et al : Phase II trial of cetuximab and carboplatin in relapsed platinum-sensitive ovarian cancer and evaluation of epidermal growth factor receptor expression : a Gynecologic Oncology Group study. Gynecol Oncol 108 : 493─499, 2008

18） Van Cutsem E, Lang I, D’haens G, et al : KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer（mCRC）treated with FOLFIRI with or without cetuximab : The CRYSTAL experience. Proc Am Soc Clin Oncol 26 : 5s #2, 2008

19） Romond EH, Perez EA, Bryant J, et al : Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 20 : 1673─1684, 2005

20） Hellström I, Goodman G, Pullman J, et al : Overexpression of HER-2 in ovarian carcinomas. Cancer Res 15 : 2420─2423, 2001

21） Bookman MA, Darcy KM, Clarke-Pearson D, et al : Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2 : a phase II trial of the Gynecologic Oncology Group. J Clin Oncol 15 : 283─290, 2003

22） Gordon MS, Matei D, Aghajanian C, et al : Clinical activity of pertuzumab（rhuMAb 2C4），a HER dimerization inhibitor, in advanced ovarian cancer : potential predictive relationship with tumor HER2 activation status. J Clin Oncol 10 : 4324─4332, 2006

23） Makhija S, Amler LC, Glenn D, et al : Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol 28 : 1215─1223, 2010

24） Kanamori Y, Kigawa J, Itamochi H, et al : Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma. Clin Cancer Res 7 : 892─895, 2001

25） Grünwald V, DeGraffenried L, Russel D, et al : Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res 62 : 6141─6145, 2002

26） Audeh MW, Carmichael J, Penson RT, et al : Oral poly（ADP-ribose）polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer : a proof-of-concept trial. Lancet 376 : 245─251, 2010

27） 板持広明，大山賢治，紀川純三 : 分子標的治療薬の現況と将来展望2．分子標的治療薬の現状 産婦の実際58 : 425─429, 2009

28） Ramalingam SS, Maitland ML, Frankel P, et al : Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol 28 : 56─62, 2010

29） Modesitt SC, Sill M, Hoffman JS, et al : A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma : a Gynecologic Oncology Group study. Gynecol Oncol 109 : 182─186, 2008

30） Armstrong DA, Bicher A, Coleman RL, et al : Exploratory phase II efficacy study of MORAb-003, a monoclonal antibody against folate receptor alpha, in platinum-sensitive ovarian cancer in first relapse. Proc Am Soc Clin Oncol 26 : 292s #5500, 2008