崔然 許青
(同濟(jì)大學(xué)附屬第十人民醫(yī)院腫瘤科 上海 200072)
鉑類藥物是20世紀(jì)60年代開始開發(fā)的一類抗癌藥物[1]。與烷化劑、抗癌抗生素和激素一樣,鉑類藥物也屬于細(xì)胞周期非特異性藥物。鉑類藥物進(jìn)入腫瘤細(xì)胞后能與DNA形成Pt-DNA加合物,從而介導(dǎo)腫瘤細(xì)胞壞死或凋亡、產(chǎn)生抗癌效果。自1978年順鉑(cisplatin)上市以來,許多新型鉑類藥物相繼問世,為抗癌治療提供了新的選擇。經(jīng)過將近半個世紀(jì)的發(fā)展,鉑類藥物因其獨(dú)特的抗癌機(jī)制、廣泛的抗癌譜而成為抗癌藥物研究的熱點(diǎn)之一。順鉑和卡鉑(carboplatin)是目前臨床上使用最廣的化療藥物之一,被廣泛用于治療非小細(xì)胞肺癌(non-small-cell lung cancer, NSCLC)、卵巢癌、宮頸癌、食管癌、胃癌、結(jié)腸直腸癌和頭頸部腫瘤等常見惡性腫瘤。隨著藥物表觀基因組學(xué)(pharmacoepigenomics)的發(fā)展,對新的分子標(biāo)志物的探索將為未來降低癌癥患者對鉑類藥物的耐藥性以及增強(qiáng)療效、提高生存率提供新的契機(jī)。
NSCLC是最常見的肺癌病理類型,約占全部肺癌的80%~85%。貝伐珠單抗(bevacizumab)通過選擇性地與人血管內(nèi)皮生長因子(vascular endothelial growth factor, VEGF)結(jié)合阻斷VEGF的生物活性,進(jìn)而抑制血管增殖。Du等[2]報(bào)告,在一項(xiàng)治療NSCLC患者惡性胸腔積液的臨床試驗(yàn)中,貝伐珠單抗300 mg聯(lián)合順鉑30 mg能較單用順鉑30 mg更有效地降低積液中的VEGF和癌胚抗原(carcinoembryonic antigen)含量,而兩組3~4級不良事件的發(fā)生率沒有顯著差異,推測胸腔積液中的VEGF水平可能可作為貝伐珠單抗治療的預(yù)后標(biāo)志。Urata等[3]在一項(xiàng)Ⅱ期試驗(yàn)中使用S-1聯(lián)合卡鉑和貝伐珠單抗治療48例NSCLC患者,結(jié)果顯示客觀緩解率(objective response rate, ORR)為54.2%(95%CI: 39.2%~68.6%)、中位無進(jìn)展生存時間(progressionfree survival, PFS)為 6.8個 月(95% CI: 4.3~ 8.2個月),≥3級的毒性主要為血液毒性。在日本進(jìn)行的一項(xiàng)Ⅱ期試驗(yàn)(“JO19907”試驗(yàn))發(fā)現(xiàn),貝伐珠單抗聯(lián)合卡鉑和紫杉醇治療晚期NSCLC患者(121例)可較單用卡鉑和紫杉醇(59例)顯著提高ORR(分別為60.7%和31.0%,P=0.001 3),且治療組和對照組均未出現(xiàn)新的嚴(yán)重副作用[4]。
與貝伐珠單抗類似,莫特塞尼(motesanib)亦具有抗VEGF受體-1,VEGF受體-2,VEGF受體-3、血小板衍生生長因子受體(platelet-derived growth factor receptor, PDGFR)和Kit的作用。Blumenschein等[5]通過一項(xiàng)Ⅱ期多中心、對照試驗(yàn)比較了莫特塞尼聯(lián)合紫杉醇和卡鉑與貝伐珠單抗聯(lián)合紫杉醇和卡鉑治療晚期非鱗癌NSCLC的療效和耐受性,發(fā)現(xiàn)兩治療組的療效相當(dāng),但在莫特塞尼組中出現(xiàn)了較高的毒性反應(yīng),盡管毒性反應(yīng)仍在可控范圍內(nèi)。厄洛替尼(erlotinib)通過阻斷表皮生長因子受體(epidermal growth factor receptor, EGFR)信號途徑產(chǎn)生抗腫瘤增殖和侵襲作用。Chen等[6]評估了國內(nèi)一項(xiàng)關(guān)于厄洛替尼治療NSCLC的Ⅲ期隨機(jī)、開放性試驗(yàn)(“CTONG-0802”試驗(yàn))中EGFR突變陽性患者的生存質(zhì)量后發(fā)現(xiàn),厄洛替尼在延長PFS、改善生存質(zhì)量方面優(yōu)于吉西他濱聯(lián)合卡鉑。
紫杉烷類藥物因具有抗微管作用而成為鉑類藥物治療NSCLC的常用配伍藥物。Xie等[7]的研究表明,樂鉑(lobaplatin)單用或聯(lián)合抗微管藥物(特別是多西他賽)的抗NSCLC活性較順鉑或卡鉑高。最近完成的一項(xiàng)治療NSCLC的6國多中心Ⅲ期臨床試驗(yàn)(“CA031”試驗(yàn))表明,與紫杉醇(paclitaxel)聯(lián)合卡鉑相比,130 nm白蛋白-紫杉醇顆粒(130 nm albumin-bound paclitaxel particles)聯(lián)合卡鉑治療可以顯著提高ORR(分別為35%和27%)、延長中位PFS(分別為6.9和5.6個月,HR=0.845)和中位總生存期(overall survival, OS)(分別為16.7和15.9個月, HR=0.930)[8]。
抗葉酸代謝藥物培美曲賽(pemetrexed)聯(lián)合順鉑或卡鉑作為ⅢB~Ⅳ期NSCLC的一線治療方案最近已在德國獲得批準(zhǔn)。Schuette等[9]進(jìn)行的一項(xiàng)Ⅱ期隨機(jī)試驗(yàn)發(fā)現(xiàn),培美曲賽聯(lián)合順鉑或卡鉑治療能夠達(dá)到較理想的目標(biāo)。培美曲塞聯(lián)合卡鉑治療老年晚期NSCLC的Ⅱ期試驗(yàn)也正在法國進(jìn)行[10]。
1.2.1 治療乳腺癌
乳腺癌、特別是已發(fā)生轉(zhuǎn)移的乳腺癌對蒽環(huán)類或紫杉烷類藥物不敏感。Deng等[11]進(jìn)行的Ⅱ期試驗(yàn)評價了樂鉑35 mg/m2聯(lián)合培美曲賽500 mg/m2治療對蒽環(huán)類和紫杉烷類藥物耐藥的轉(zhuǎn)移性乳腺癌的療效和安全性,結(jié)果顯示部分緩解率為15.8%(3/19)、中位OS為10.3個月,但因各種毒性反應(yīng)率高,藥物劑量有待調(diào)整。三陰乳腺癌(triple-negative breast cancer, TNBC)是指雌激素受體、孕激素受體和人表皮生長因子受體-2(human epidermal growth factor receptor-2)均為陰性的乳腺癌,約占所有乳腺癌的15%,預(yù)后差[12]。近期美國一項(xiàng)回顧性分析表明,順鉑聯(lián)合多西他賽延長局部進(jìn)展TNBC患者PFS和OS的作用優(yōu)于卡鉑[13]。
1.2.2 治療宮頸癌
宮頸癌是導(dǎo)致女性死亡的第二大癌癥死因,65歲以上婦女的宮頸癌發(fā)病率為0.69%~1.38%[14],順鉑被推薦用于治療復(fù)發(fā)的宮頸癌已有30年歷史[15],順鉑聯(lián)合紫杉醇一直是治療進(jìn)展期和復(fù)發(fā)的宮頸癌的一線化療方案。來自如婦科腫瘤組織(Gynecologic Oncology Group)、日本臨床腫瘤組織(Japanese Clinical Oncology Group)等國際協(xié)作組織的數(shù)據(jù)顯示,順鉑聯(lián)合紫杉醇仍然是目前治療進(jìn)展期和復(fù)發(fā)的宮頸癌的最優(yōu)方案,而卡鉑可能是未來替代順鉑治療宮頸癌的理想藥物[16]。
1.2.3 治療卵巢癌
p53突變和Akt活化導(dǎo)致的對鉑類藥物的耐藥現(xiàn)象在治療卵巢癌時很常見,提高卵巢癌細(xì)胞的敏感性及尋找新的聯(lián)合治療方案是當(dāng)務(wù)之急。Kobayashi等[17]的研究發(fā)現(xiàn),p53再激活并誘導(dǎo)大規(guī)模細(xì)胞凋亡-1(p53 reactivation and induction of massive apoptosis-1)可以增加p53突變的耐藥性卵巢癌細(xì)胞對順鉑化療的敏感性,這可能是通過增加磷酸化p53的含量和下調(diào)Akt的表達(dá)、進(jìn)而促進(jìn)癌細(xì)胞凋亡來實(shí)現(xiàn)的。類似地,韓國研究人員通過使用鹽霉素(salinomycin)抑制蛋白激酶B即Akt/轉(zhuǎn)錄因子-κB信號分子而成功地使耐順鉑卵巢癌細(xì)胞(A2780cis)發(fā)生了凋亡[18]。這些研究為解決卵巢癌耐藥問題提供了新的思路和方法。
1.3.1 治療胃癌
順鉑聯(lián)合氟尿嘧啶(fluorouracil)是治療晚期胃腺癌的常用方案。順鉑聯(lián)合氟尿嘧啶和多西他賽(DCF方案)的Ⅱ/Ⅲ期臨床試驗(yàn)表明,該方案的療效更好,但血液毒性也大大增加。Alici等[19]使用低劑量DCF方案治療120例轉(zhuǎn)移性胃癌獲得了較好的療效:4例達(dá)到完全緩解、36例達(dá)到部分緩解,ORR為56.6%;中位到疾病進(jìn)展時間為7個月(95% CI: 6~7.9個月),中位OS為15個月(95% CI: 13.7~16.2個月);3~4級白細(xì)胞減少發(fā)生率為20%(24/120)。索拉非尼(sorafenib)通過抑制VEGF受體和PDGFR等多種受體的酪氨酸激酶產(chǎn)生抗血管生成作用。近期完成的一項(xiàng)Ⅱ期試驗(yàn)(“ECOG 5203”試驗(yàn))探索了索拉非尼聯(lián)合順鉑和多西他賽治療轉(zhuǎn)移性或晚期胃癌和胃食管交界處腺癌的療效,發(fā)現(xiàn)有41%(18/44)的患者達(dá)到部分緩解,中位PFS為5.8個月,中位OS為13.6個月[20]。雖然有64%的患者出現(xiàn)了3~4級白細(xì)胞減少,但該聯(lián)合方案的療效和耐受性值得進(jìn)一步探索。
1.3.2 治療結(jié)腸直腸癌
結(jié)腸直腸癌在確診時有20%~25%的患者已發(fā)生肝轉(zhuǎn)移[21]。奧沙利鉑是第一個顯現(xiàn)對結(jié)腸癌有效的鉑類藥物,其聯(lián)合氟尿嘧啶和亞葉酸(leucovorin)(FOLFOX方案)是治療結(jié)腸癌的常用方案。日本的一項(xiàng)回顧性研究和歐洲的多項(xiàng)臨床試驗(yàn)均表明,F(xiàn)OLFOX方案可以有效治療結(jié)腸直腸癌[22]。Shogbon等[23]最近報(bào)告了1例因使用FOLFOX方案化療導(dǎo)致結(jié)腸癌患者隱源性機(jī)化性肺炎(cryptogenic organizing pneumonia)的罕見病例,該不良事件應(yīng)引起臨床醫(yī)師的注意。
1.3.3 治療頭頸部腫瘤
近10年來頭頸部腫瘤的發(fā)病率有所上升,其病理類型以鱗癌為主。2011年美國FDA批準(zhǔn)了西妥昔單抗(cetuximab)聯(lián)合順鉑(卡鉑)和氟尿嘧啶作為局部復(fù)發(fā)或轉(zhuǎn)移性頭頸部鱗癌的一線治療方案。Cohen等[24]使用歐盟批準(zhǔn)的西妥昔單抗對此方案進(jìn)行驗(yàn)證,獲得了較好的療效。Huang等[25]比較了西妥昔單抗聯(lián)合放療與鉑類藥物聯(lián)合放療治療頭頸部腫瘤的療效,發(fā)現(xiàn)這兩方案在改善2年局部復(fù)發(fā)率和遠(yuǎn)處轉(zhuǎn)移方面沒有差異,但鉑類藥物聯(lián)合放療可顯著延長≤65歲患者的2年生存率(分別為83%和58%,P=0.001)。西妥昔單抗聯(lián)合放療可能是治療老年頭頸部腫瘤的合理替代方案。日本的一項(xiàng)使用鉑類藥物聯(lián)合西妥昔單抗治療33例復(fù)發(fā)和轉(zhuǎn)移的頭頸部鱗癌的Ⅱ期臨床試驗(yàn)也取得了較好療效(中位PFS為4.1個月,OS為14.1個月,疾病控制率為88%),但97%的患者出現(xiàn)了3~4級不良事件,提示需對此方案進(jìn)行進(jìn)一步研究以降低毒性[26]。
藥物表觀基因組學(xué)是指基于表觀遺傳學(xué)的機(jī)制來研究藥物基因組學(xué)對藥物反應(yīng)性的調(diào)節(jié),對探究耐鉑類藥物機(jī)制和增強(qiáng)鉑類藥物的抗癌效果意義重大。近年來的研究表明,許多分子生物學(xué)標(biāo)志物參與了鉑類藥物的抗癌作用過程。
1)核苷酸切除修復(fù)交叉互補(bǔ)組-1(excision repair cross-complmenting group-1, ERCC1)ERCC1是核苷酸減切修復(fù)(nucleotide excision repair)途徑的關(guān)鍵因子,與對鉑類藥物抵抗有很強(qiáng)的相關(guān)性[27-29],即ERCC1表達(dá)水平的高低與鉑類藥物的抗癌療效和患者預(yù)后呈負(fù)相關(guān)關(guān)系。近期Lu等[30]的研究對此理論提出了挑戰(zhàn),他們發(fā)現(xiàn)直腸癌伴淋巴結(jié)轉(zhuǎn)移者有較無淋巴結(jié)轉(zhuǎn)移者更低的ERCC1以及乳腺和卵巢癌易感基因-1(breast and ovarian cancer susceptibility-1, BRCA1)mRNA水平,推測ERCC1和BRCA1的低表達(dá)可作為直腸癌不良預(yù)后的預(yù)測因子。
2)BRCA1 BRCA1涉及多種DNA修復(fù)途徑,完整的BRCA1路徑對于修復(fù)DNA交叉鏈接和斷裂起著重要作用,而該路徑受損則常意味著DNA修復(fù)能力下降、對順鉑治療敏感[31]。一項(xiàng)多中心Ⅲ期隨機(jī)試驗(yàn)(“GOG-172”試驗(yàn))研究了順鉑聯(lián)合紫杉醇靜脈內(nèi)給藥和腹腔內(nèi)給藥治療Ⅲ期卵巢上皮癌的療效,發(fā)現(xiàn)在BRCA1表達(dá)正常組,兩種給藥途徑的中位OS沒有差異(分別為50和58個月,P=0.818)。但在BRCA1表達(dá)異常組,兩種給藥途徑的中位OS差異明顯(分別為47和84個月,P=0.000 2)[32],這可能與BRCA1的低表達(dá)增強(qiáng)了卵巢上皮癌對順鉑聯(lián)合紫杉醇腹腔內(nèi)給藥的敏感性有關(guān)。
除ERCC1和BRCA1外,一些其他分子生物學(xué)標(biāo)志物如胰島素樣生長因子結(jié)合蛋白-3 (insulin-like growth factor binding protein-3)、谷胱甘肽S-轉(zhuǎn)移酶(glutathioneS-transferase)、跨膜蛋白158(transmembrane protein 158)和細(xì)絲結(jié)合LIM蛋白-1(filamin-binding LIM protein-1)與鉑類藥物抗癌效果間的關(guān)系也在研究中,未來有望對腫瘤患者實(shí)現(xiàn)更有效的個體化治療。
[1]Gómez-Ruiz S, Maksimovi?-Ivani? D, Mijatovi? S,et al.On the discovery, biological effects, and use of cisplatin and metallocenes in anticancer chemotherapy [J/OL]. Bioinorg Chem Appl, 2012, 2012: 140284 [2013-08-01]. http://downloads.hindawi.com/journals/bca/2012/140284.pdf.
[2]Du N, Li X, Li F,et al. Intrapleural combination therapy with bevacizumab and cisplatin for non-small-cell lung cancermediated malignant pleural effusion [J]. Oncol Rep,2013, 29(6): 2332-2340.
[3]Urata Y, Okamoto I, Takeda M,et al. Phase 2 study of S-1 and carboplatin plus bevacizumab followed by maintenance S-1 and bevacizumab for chemotherapy-naive patients with advanced nonsquamous non-small cell lung cancer [J].Cancer, 2013, 119(12): 2275-2281.
[4]Niho S, Kunitoh H, Nokihara H,et al. Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced nonsquamous non-small-cell lung cancer [J]. Lung Cancer, 2012,76(3): 362-367.
[5]Blumenschein GR Jr, Kabbinavar F, Menon H,et al. A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer [J].Ann Oncol, 2011, 22(9): 2057-2067.
[6]Chen G, Feng J, Zhou C,et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised,open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-smallcell lung cancer (NSCLC) [J]. Ann Oncol, 2013, 24(6): 1615-1622.
[7]Xie CY, Xu YP, Jin W,et al. Antitumor activity of lobaplatin alone or in combination with antitubulin agents in non-smallcell lung cancer [J]. Anticancer Drugs, 2012, 23(7): 698-705.
[8]Satouchi M, Okamoto I, Sakai H,et al. Efficacy and safety of weekly nab-paclitaxel plus carboplatin in patients with advanced non-small cell lung cancer [J]. Lung Cancer, 2013,81(1): 97-101.
[9]Schuette WH, Groschel A, Sebastian M,et al. A randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line therapy for patients with locally advanced or metastatic non-small-cell lung cancer [J]. Clin Lung Cancer, 2013, 14(3): 215-223.
[10]Gervais R, Robinet G, Clément-Duchêne C,et al. Pemetrexed and carboplatin, an active option in first-line treatment of elderly patients with advanced non-small-cell lung cancer(NSCLC): a phase II trial [J]. Lung Cancer, 2013, 80(2): 185-190.
[11]Deng QQ, Huang XE, Ye LH,et al. Phase II trial of Loubo(lobaplatin) and pemetrexed for patients with metastatic breast cancer not responding to anthracycline or taxanes [J]. Asian Pac J Cancer Prev, 2013, 14(1): 413-417.
[12]Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review [J]. Histopathology, 2008, 52(1): 108-118.
[13]Hurley J, Reis IM, Rodgers SE,et al. The use of neoadjuvant platinum-based chemotherapy in locally advanced breast cancer that is triple negative: retrospective analysis of 144 patients [J]. Breast Cancer Res Treat, 2013, 138(3): 783-794.
[14]Scatchard K, Forrest JL, Flubacher M,et al. Chemotherapy for metastatic and recurrent cervical cancer [J/OL]. Cochrane Database Syst Rev, 2012, 10: CD006469 [2013-06-01].http://onlinelibrary.wiley.com.libauth.mskcc.org:2048/doi/10.1002/14651858.CD006469.pub2/pdf.
[15]Bonomi P, Blessing JA, Stehman FB,et al. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study [J]. J Clin Oncol, 1985, 3(8): 1079-1085.
[16]Leath CA 3rd, Straughn JM Jr. Chemotherapy for advanced and recurrent cervical carcinoma: results from cooperative group trials [J]. Gynecol Oncol, 2013, 129(1): 251-257.
[17]Kobayashi N, Abedini M, Sakuragi N,et al. PRIMA-1 increases cisplatin sensitivity in chemoresistant ovarian cancer cells withp53mutation: a requirement for Akt downregulation [J]. J Ovarian Res, 2013, 6(1): 7-12.
[18]Parajuli B, Lee HG, Kwon SH,et al. Salinomycin inhibits Akt/NF-kappaB and induces apoptosis in cisplatin resistant ovarian cancer cells [J]. Cancer Epidemiol, 2013, 37(4): 512-517.
[19]Alici S, Buyukberber S, Alkis N,et al. Low-dose docetaxel/cisplatin-leucovorin and 46 hour infusional fluorouracil in metastatic gastric carcinoma [J]. Asian Pac J Cancer Prev,2013, 14(1): 423-427.
[20]Sun WJ, Powell M, O’Dwyer PJ,et al. Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203 [J]. J Clin Oncol, 2010, 28(18): 2947-2951.
[21]Ochiai T, Masuda T, Yagi M,et al. Successful combination therapy of radical liver resection with 5-fluorouracil/leucovorin, oxaliplatin, plus bevacizumab for ascending colon cancer with pulmonary and 43 liver metastases: report of a case [J]. Int Surg, 2012, 97(1): 6-13.
[22]Yoshida M, Goto M, Kii T,et al. Retrospective study as first-line chemotherapy combined anti-VEGF antibody with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer [J]. Digestion, 2013, 87(1): 59-64.
[23]Shogbon AO, Hap J, Dretler R,et al. Cryptogenic organizing pneumonia during adjuvant chemotherapy with oxaliplatin,5-fluorouracil, and leucovorin (FOLFOX) for colon cancer[J]. J Pharm Pract, 2013, 26(1): 62-66.
[24]Cohen MH, Chen H, Shord S,et al. Approval summary:cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer [J]. Oncologist, 2013, 18(4): 460-466.
[25]Huang J, Baschnagel AM, Chen P,et al. A matched-pair comparison of intensity-modulated radiation therapy with cetuximab versus intensity-modulated radiation therapy with platinum-based chemotherapy for locally advanced head neck cancer [J]. Int J Clin Oncol, 2013, 6(7): 1-7.
[26]Yoshino T, Hasegawa Y, Takahashi S,et al. Platinum-based chemotherapy plus cetuximab for the first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: results of a phase II trial[J]. Jpn J Clin Oncol, 2013, 43(5): 524-531.
[27]Tiseo M, Bordi P, Bortesi B,et al. ERCC1/BRCA1 expression and gene polymorphisms as prognostic and predictive factors in advanced NSCLC treated with or without cisplatin [J]. Br J Cancer, 2013, 108(8): 1695-1703.
[28]Liu YP, Ling Y, Qi QF,et al. The effects of ERCC1 expression levels on the chemosensitivity of gastric cancer cells to platinum agents and survival in gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy [J]. Oncol Lett,2013, 5(3): 935-942.
[29]Lee SH, Noh KB, Lee JS,et al. Thymidylate synthase and ERCC1 as predictive markers in patients with pulmonary adenocarcinoma treated with pemetrexed and cisplatin [J].Lung Cancer, 2013, 81(1): 102-108.
[30]Lu YM, Zhang LN, Song BR,et al. BRCA1 and ERCC1 mRNA levels are associated with lymph node metastasis in Chinese patients with colorectal cancer [J]. BMC Cancer,2013, 13(3): 103-110.
[31]Hegi ME, Sciuscio D, Murat A,et al. Epigenetic deregulation of DNA repair and its potential for therapy [J]. Clin Cancer Res, 2009, 15(16): 5026-5031.
[32]Lesnock JL, Darcy KM, Tian C,et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group study [J]. Br J Cancer, 2013, 108(6): 1231-1237.