Inhibition of renin–angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine

Nakai, Yousuke; Isayama, Hiroyuki; Ijichi, Hideaki; Sasaki, Takashi; Sasahira, Naoki; Hirano, Keisuke; Kogure, Hirofumi; Kawakubo, Kazumichi; Yagioka, Hiroshi; Yashima, Yoko; Mizuno, Suguru; Yamamoto, Keisuke; Arizumi, Toshihiko; Togawa, Osamu; Matsubara, Saburo; Tsujino, Takeshi; Tateishi, Keisuke; Tada, Minoru; Omata, Masao; Koike, Kazuhiko

doi:10.1038/sj.bjc.6605955

Cited by 149 publications

(150 citation statements)

References 33 publications

(38 reference statements)

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“…(13) In the retrospective analysis, although the objective response did not increase by the inhibition of RAS, PFS of 8.7 months in patients receiving ACEIs or ARBs was superior to that in patients who did not receive ACEIs or ARBs. The primary endpoint of this phase I study was safety and the analysis of efficacy was difficult with a small sample, but a disease control rate as high as 79% despite the response rate of 0%, and PFS of 7.6 months, was promising.…”

Section: Discussionmentioning

confidence: 99%

“…(13) Candesartan was the most often used antihypertensive medication in the retrospective study and is reported to have the most potent selective ARB. Furthermore, when we treated a genetically engineered mouse model of pancreatic cancer (16) with several ARBs, candesartan clearly inhibited VEGF expression and angiogenesis in vivo and showed a better tendency of survival extension compared with other ARBs (Motohisa Tada, Hideaki Ijichi, Koji Miyabayashi, Yoshinari Asaoka, Dai Mohri, Tsuneo Ikenoue, Keisuke Tateishi, Yasuyuki Morishita, Rintarou Mikata, Takeshi Ishihara, Fumihiko Kanai, Fumio Imazeki, Masao Omata, Harold L. Moses, Osamu Yokosuka, unpublished data, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…(10) In addition, the inhibition of RAS is reported to induce apoptosis in pancreatic cancer cells. (11,12) Our retrospective study (13) showed the inhibition of RAS by the use of ACEIs or ARBs for hypertension was associated with longer progression-free survival (PFS) or OS in patients with advanced pancreatic cancer receiving gemcitabine. Similar results were reported in non-small-cell lung cancer and renal cell cancer.…”

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confidence: 99%

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Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1

et al. 2012

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Our retrospective study showed inhibition of the renin-angiotensin system was associated with better outcomes in patients with advanced pancreatic cancer receiving gemcitabine. The primary objective of this phase I study was to determine the recommended dose of candesartan in combination with gemcitabine in normotensive patients with advanced pancreatic cancer. Candesartan was given orally at an escalating dose (4,8,16, and 32 mg) q.d. daily, and gemcitabine was given 1000 mg/m 2 30 min i.v. on days 1, 8, and 15, repeated every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicities, grade 2 hypotension, abnormal creatinine or potassium, and grade 3 or 4 other non-hematological toxicities. A standard "3+3" phase I dose-escalation design was used. A total of 14 patients (candesartan 4 mg, three patients; 8 mg, three patients; 16 mg, six patients; 32 mg, two patients) were enrolled. One of six patients at 16 mg showed DLT of grade 4 neutropenia and two of two patients at 32 mg showed DLT of grade 2 hypotension. Response rate and disease control rate were 0% and 79%, respectively. Progression-free survival and overall survival were 7.6 and 22.9 months, respectively. Candesartan 16 mg is the recommended dose in combination with gemcitabine in the treatment of advanced pancreatic cancer. (UMIN CTR: UMIN000002152) (Cancer Sci 2012; 103: 1489-1492 G emcitabine was shown to improve overall survival (OS) compared with 5-fluorouracil in advanced pancreatic cancer,(1) therefore, extensive research of combination therapy using gemcitabine with other cytotoxic drugs or molecular targeted drugs has been carried out. No single randomized controlled trial indicated superiority in OS of gemcitabine combined with other cytotoxic drugs compared with gemcitabine monotherapy. Recently, FOLFIRINOX, (2) a multiagent regimen without gemcitabine, prolonged OS significantly but serious adverse events such as febrile neutropenia also increased. Among molecular target agents, only erlotinib in combination with gemcitabine showed modest improvement in OS (3) and other agents including cetuximab, (4) bevacizumab,and axitinib (6) failed to demonstrate benefits in OS in phase III trials.The systemic renin-angiotensin system (RAS) is associated with cardiovascular regulation and angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) are the most widely used antihypertensive drugs. Since Lever et al. (7) reported that the use of ACEIs was associated with a decreased incidence of cancer in a large cohort study, the potential role of the local RAS in carcinogenesis has attracted substantial attention. The local RAS reportedly promotes angiogenesis and cellular proliferation through vascular endothelial growth factor (VEGF) expression or epidermal growth factor receptor expression.(8,9) Synergistic inhibition of tumor growth in a murine pancreatic cancer has been shown with combined gemcitabine and losartan treatment through VEGF suppression. (10) In addition, the inhibiti...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1

et al. 2012

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“…Furthermore, it has been reported that the addition of ACE-I or ARB provided the prolonged survival for the patients with advanced non-small cell lung cancer undergoing platinum-based chemotherapy [41]. Additionally, inhibition of RAAS possibly exerted the beneficial effects on the prognosis of patients with advanced hormone-refractory prostate cancer and pancreatic cancer receiving gemcitabine [42,43]. In regard to liver cancer, ACE-I showed the suppressive effect on the tumor growth in a murine HCC experimental model [44].…”

Section: Raas Blockersmentioning

confidence: 99%

Antiangiogenic Therapy for Hepatocellular Carcinoma

Kaji¹,

Yoshiji²

2017

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

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Angiogenesis plays a pivotal role in many pathological processes, including hepatocellular carcinoma (HCC). This indicates that antiangiogenic agents could be promising candidates for chemoprevention against HCC. Several inhibitors targeting receptor tyrosine kinases (RTKs) for the regulation of tumoral vascularization have been developed and employed in clinical practice, including sorafenib. However, there seem to be several issues for the long-term use of this agent as some patients have experienced adverse effects while taking sorafenib. Therefore, it is desirable for patients with chronic liver diseases to be administered sorafenib as little as possible by combining other safe-to-use antiangiogenic compounds. Various factors, such as renin-angiotensin-aldosterone system (RAAS) and insulin resistance (IR), reciprocally contribute to the promotion of angiogenesis. A blockade of RAAS with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin-II (AT-II) receptor blocker (ARB) markedly attenuates HCC in conjunction with the suppression of angiogenesis. Moreover, the IR status has demonstrated direct acceleration in the progression of HCC via the augmentation of tumoral neovascularization. These findings suggest that a combination therapy involving a lower dose of sorafenib with other clinically used agents [e.g., RAAS blockers, insulin sensitizer agents, and branched-chain amino acids (BCAA)] may reduce the adverse effects of sorafenib without attenuating the inhibitory effect against HCC in comparison to a high-dose administration.

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“…There are a number of studies investigating the effects of these drugs and cancer treatments: For instance, metformin has been epidemiologically demonstrated to suppress tumor metastasis (83,84), whereas Nakai et al (85) demonstrated that inhibition of the renin-angiotensin system affects the prognosis of patients with advanced pancreatic cancer receiving GEM. A number of studies have focused on the inhibition of tumor EMT and stromal cell activation using paclitaxel (74,86,87).…”

Section: Effect Of Preoperative Therapy On Pancreatic Cancer Tissuesmentioning

confidence: 99%

Neoadjuvant chemotherapy for pancreatic cancer: Effects on cancer tissue and novel perspectives

et al. 2017

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Abstract. Chemotherapy for pancreatic cancer has diversified following the addition of more treatment regimens; however, in spite of this, pancreatic cancer remains a fatal disease. Preoperative (neoadjuvant) chemotherapy (NAC) or neoadjuvant chemoradiation therapy (NACRT) has been developed and implemented. For patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), a number of clinical trials have been conducted; NACRT was demonstrated to improve resectability, R0 resection rate, overall survival rate, disease-free survival rate and even an LAPC and BRPC survival advantage over NAC. However, from the knowledge obtained from resected specimens following preoperative treatment, residual pancreatic cancer tissues following NAC are rich in chemoresistant cancer stem-like cells and epithelial-mesenchymal transition (EMT) markers. Conversely, metformin, angiotensin receptor blocker, statins and low-dose paclitaxel are well-known as drugs that inhibit EMT, which is associated with cancer stem cell-like characteristics. Although clinical effectiveness is unlikely to be achieved using one of these as an anticancer agent, it is reasonable to use these drugs for patients with comorbidities in the treatment of pancreatic cancer. Furthermore, gemcitabine (GEM) affects antitumor immunity by stimulating the expression of major histocompatibility complex class I-related chain A on the surface of cancer cells to enhance the cytotoxicity of natural killer cells. Considering EMT and antitumor immunity, there is a possibility that GEM and nanoparticle albumin-bound paclitaxel therapy is the most suitable regimen for treating pancreatic cancer. However, even as preoperative treatment progresses, R0 resection is the most important factor for the long-term survival of pancreatic cancer patients.

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Inhibition of renin–angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine

Cited by 149 publications

References 33 publications

Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1

Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1

Antiangiogenic Therapy for Hepatocellular Carcinoma

Neoadjuvant chemotherapy for pancreatic cancer: Effects on cancer tissue and novel perspectives

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