臨床泌尿器科63巻1号

2009年01月発行

綜説

腎細胞癌に対する分子標的治療の展開

著者： 湯浅健¹ 土谷順彦¹ 羽渕友則¹

所属機関： ¹秋田大学医学部泌尿器科

ページ範囲：P.7 - P.13

文献概要

要旨　腎細胞癌は根治的腎摘術が唯一確実な治療手段であり，抗癌剤による化学療法や放射線治療に抵抗性を示すことから遠隔転移を有するなど外科的摘除不能症例は予後不良である。治癒摘除不能例，遠隔転移症例ではインターフェロンやインターロイキン2などによる免疫療法が行われるが，奏効率は低く，10～20％とされている。このように既存の治療法の効果が乏しい腎細胞癌に対して，最近，癌細胞に特異的な異常を治療の標的とした「分子標的治療（molecular target therapy）」という新しい概念の癌治療法が注目されている。ゲノム創薬を駆使して開発された分子標的治療薬が転移性腎細胞癌に対して承認され，臨床で使用されるようになった。本稿では，分子標的治療薬の抗腫瘍作用のメカニズムから代表的臨床試験結果，治療効果の予測，および現在進行中の臨床試験まで，現在の知見や情報を概説する。

参考文献

1）Campbell SC, Novick AC and Bukowski RM：Renal tumors. In：Campbell-Walsh Urology. edited by Wein AJ, Kavoussi LR, Novick AC, et al. Saunders, New York, pp1567-1637, 2007

2）Cohen HT and McGovern FJ：Renal-cell carci-noma. N Engl J Med 353：2477-2490, 2005

3）Larkin JM, Chowdhury S and Gore ME：Drug insight：advances in renal cell carcinoma and the role of targeted therapies. Nat Clin Pract Oncol 4：470-479, 2007

4）Bratslavsky G, Sudarshan S, Neckers L, et al：Pseudohypoxic pathways in renal cell carcinoma. Clin Cancer Res 13：4667-4671, 2007

5）Linehan WM, Pinto PA, Srinivasan R, et al：Identification of the genes for kidney cancer：opportunity for disease-specific targeted therapeutics. Clin Cancer Res 13：671s-679s, 2007

6）Krause DS and Van Etten RA：Tyrosine kinases as targets for cancer therapy. N Engl J Med 353：172, 2005

7）Escudier B, Pluzanska A, Koralewski P, et al：AVOREN trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma：a randomised, double-blind phase Ⅲ trial. Lancet 370：2103-2111, 2007

8）Escudier B, Eisen T, Stadler WM, et al：TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356：125-134, 2007

9）Motzer RJ, Hutson TE, Tomczak P, et al：Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356：115-124, 2007

10）Rixe O, Bukowski RM, Michaelson MD, et al：Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer：a phase Ⅱ study. Lancet Oncol 8：975-984, 2007

11）Hudes G, Carducci M, Tomczak P, et al：Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356：2271-2281, 2007

12）Flanigan RC, Salmon SE, Blumenstein BA, et al：Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345：1655-1659, 2001

13）Mickisch GH, Garin A, van Poppel H, et al：European Organisation for Research and Treatment of Cancer（EORTC）Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma：a randomised trial. Lancet 358：966-970, 2001

14）Eisen T：Adjuvant therapy in renal cell carcinoma：what are we? Eur Urol Supple 6：492-498, 2007

15）Choueiri TK, Garcia JA, Elson P, et al：Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted thera-py. Cancer 110：543-550, 2007

16）Willett CG, Boucher Y, Duda DG, et al：Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy：continued experience of a phase Ⅰ trial in rectal cancer patients. J Clin Oncol 23：8136-8139, 2005

17）Ebos JM, Lee CR, Christensen JG, et al：Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 104：17069-17074, 2007

18）Chen W, Delaloye S, Silverman DH, et al：Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with［18F］fluorothymidine positron emission tomography：a pilot study. J Clin Oncol 25：4714-4721, 2007

19）Flaherty KT, Rosen MA, Heitjan DF, et al：Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma. Cancer Biol Ther 7：496-501, 2008

20）Ito N, Eto M, Nakamura E, et al：STAT3 polymorphism predicts interferon-alfa response in patients with metastatic renal cell carcinoma. J Clin Oncol 25：2785-2791, 2007

21）Rini BI, Jaeger E, Weinberg V, et al：Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma：impact of patient characteristics and Von Hippel-Lindau gene status. BJU Int 98：756-762, 2006

22）Badgwell BD, Camp ER, Feig B, et al：Management of bevacizumab-associated bowel perforation：a case series and review of the literature. Ann Oncol 19：577-582, 2007

23）Costa LJ and Drabkin HA：Renal cell carcinoma：new developments in molecular biology and potential for targeted therapies. Oncologist 12：1404-1415, 2007

24）Inoue A, Saijo Y, Maemondo M, et al：Severe acute interstitial pneumonia and gefitinib. Lancet 361：137-139, 2003

25）Rini BI, Tamaskar I, Shaheen P, et al：Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99：81-83, 2007

26）Chu TF, Rupnick MA, Kerkela R, et al：Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370：2011-2019, 2007