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

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
British Journal of Cancer (Impact Factor: 4.84). 10/2010; 103(11):1644-8. DOI: 10.1038/sj.bjc.6605955
Source: PubMed


The renin-angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth.
We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs).
Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis.
The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis.

Download full-text


Available from: Hideaki Ijichi, Sep 19, 2014
  • Source
    • "For example, Yamada et al. (2003) demonstrated that oral administration of candesartan (a widely used angiotensin II type-I receptor inhibitor) decreased ECM production and αSMA expression (activated PSC marker) in a rat chronic pancreatitis model. Furthermore, a retrospective clinical study suggested that pancreatic cancer patients treated with angiotensin II type 1 receptor inhibitors in combination with gemcitabine may have improved clinical outcome (Nakai et al., 2010). To expand on these findings the same authors recently completed a multicenter phase II clinical trial (35 patients with advanced pancreatic cancer) to examine whether patients treated with candesartan in combination with gemcitabine would have improved survival. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is highly chemoresistant. A major contributing factor is the characteristic extensive stromal or fibrotic reaction, which comprises up to 90% of the tumor volume. Over the last decade there has been intensive research into the role of the pro-fibrogenic pancreatic stellate cells (PSCs) and their interaction with pancreatic cancer cells. As a result of the significant alterations in the tumor microenvironment following activation of PSCs, tumor progression, and chemoresistance is enhanced. This review will discuss how PSCs contribute to chemoresistance in pancreatic cancer.
    Frontiers in Physiology 04/2014; 5:141. DOI:10.3389/fphys.2014.00141 · 3.53 Impact Factor
  • Source
    • "Furthermore, angiotensin II-receptor blockers suppressed the cell proliferation effects of AT II in breast cancer cells.71 The addition of ACE inhibitors or angiotensin II-receptor blockers to platinum-based first-line chemotherapy contributed to prolonged survival in patients with advanced lung cancer72 and positively affected the prognosis of advanced pancreatic cancer patients receiving gemcitabine.73 RAS inhibitors also improved the outcome of sunitinib treatment in metastatic renal cell carcinoma.74 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer is the leading cause of death in the USA, and the incidence of cancer increases dramatically with age. Beta-adrenergic blockers appear to have a beneficial clinical effect in cancer patients. In this paper, we review the evidence of an association between β-adrenergic blockade and cancer. Genetic studies have provided the opportunity to determine which proteins link β-adrenergic blockade to cancer pathology. In particular, this link involves the major histocompatibility complex class II molecules, the renin-angiotensin system, transcription factor nuclear factor-kappa-light-chain-enhancer of activated B cells, poly(ADP-ribose) polymerase-1, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate oxidase. Beta-adrenergic blockers also exert anticancer effects through non-genomic factors, including matrix metalloproteinase, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, oxidative stress, and nitric oxide synthase. In conclusion, β-adrenergic blockade may play a beneficial role in cancer treatment. Additional investigations that examine β-adrenergic blockers as cancer therapeutics are required to further elucidate this role.
    Cancer Management and Research 12/2012; 4:431-45. DOI:10.2147/CMAR.S39153
  • Source
    • "Wilop et al analysed retrospectively 287 patients with advanced non-small cell lung cancer undergoing first-line platinum-based chemotherapy, and reported that patients receiving either ACEIs or ARBs had a median survival that was 3.1 months longer than non-recipients (11.7 vs 8.6 months) (Wilop et al, 2009). Nakai et al reported the use of ACEIs or ARBs with gemcitabine was an independent prognostic factor for both progression-free survival and overall survival in 155 patients with advanced pancreatic cancer (Nakai et al, 2010). Two prospective studies suggested RAS inhibitor administration was effective as a salvage therapy in the treatment of prostate cancer and renal cell cancer (Uemura et al, 2005; Tatokoro et al, 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The potential role of the renin-angiotensin system (RAS) in the promotion of tumour growth has been investigated, and the administration of RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), may improve disease control in malignancy. We investigated the prognostic impact of RAS inhibitors by analysing data from patients with upper-tract urothelial carcinoma (UTUC). A total of 279 patients who underwent nephroureterectomy for localised UTUC (pTa-3N0M0) were identified at our three institutions. We retrospectively investigated the prognostic outcomes following nephroureterectomy in patients administered or not administered ACEIs or ARBs. The median follow-up period was 3.4 years. RAS inhibitors were administered to 48 patients (17.2%). Multivariate analysis showed that the appearance of pathological T3, positive lymphovascular invasion, and no RAS inhibitor administration (P=0.027 HR=3.14) were independent risk factors for a decrease in subsequent metastasis-free survival. The 5-year metastasis-free survival rate was 93.0% in patients who administered RAS inhibitors, and 72.8% in their counterparts who did not (P=0.008). The absence of RAS inhibitor administration was an independent risk factor for subsequent tumour metastasis in patients with localised UTUC. We propose RAS inhibitors may be a potent choice as an effective treatment following nephroureterectomy.
    British Journal of Cancer 12/2011; 106(2):290-6. DOI:10.1038/bjc.2011.565 · 4.84 Impact Factor
Show more