European Journal of Clinical Investigation (2004) 34, 674–682 © 2004 Blackwell Publishing Ltd Blackwell Publishing, Ltd. Novel therapeutic approach for cancer using four cardiovascular hormones D. L. Vesely *† , L. C. Clark *† , A. H. Garces *† , Q. W. McAfee *† , J. Soto † and W. R. Gower Jr *† * University of South Florida Cardiac Hormone Center, and † James A. Haley Veterans Medical Center, Tampa, FL, USA Abstract Background The atrial natriuretic peptide (ANP) gene synthesizes four cardiovascular hormones, i.e. vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and ANP, which decrease the number of human pancreatic adenocarcinoma cells in culture by 65%, 47%, 37%, and 34%, respectively. Methods and materials None of the cardiovascular hormones has been investigated to determine whether they inhibit the growth of cancers in vivo. These four hormones were evaluated for their ability to inhibit the growth of human pancreatic adenocarcinomas in athymic mice. Results Vessel dilator (139 ng min -1 kg -1 of body weight) infused for 14 days completely stopped the growth of human pancreatic adenocarcinomas in athymic mice (n = 14) with a decrease in their tumour volume, while the tumour volume increased 69-fold (P < 0·001) in the placebo (n = 30)-treated mice.When these peptide hormones (each at 1·4 μg min -1 kg -1 body weight) were infused for 4 weeks, vessel dilator, long-acting natriuretic peptide and kaliuretic peptide decreased tumour volume after 1 week by 49%, 28%, and 11%, respectively, with a one- and 20-fold increase in the tumour volume in ANP- and placebo-treated mice. Cyclic GMP (2·4 μg min -1 kg -1 body weight) inhibited after 1 week the growth of this cancer 95%. Conclusions These results suggest that these peptide hormones have useful anticancer pro- perties, as they each inhibited the growth of the human pancreatic adenocarcinomas in vivo and three of the four peptide hormones decreased the volume of the tumours (up to 49%, i.e. vessel dilator). Part of their mechanism of action appears to be mediated by cyclic GMP. Keywords Atrial natriuretic peptides, cancer, cyclic GMP, tumour suppressors, tumour volume. Eur J Clin Invest 2004; 34 (10): 674–682 Introduction Human pancreatic adenocarcinomas have the lowest 5-year survival rate of all common cancers [1,2].The 5-year survival rate of persons with adenocarcinoma of the pancreas is 1% [1,2]. The median survival is 4·1 months [1,2]. Current cancer chemotherapy and surgery prolongs survival by a few months but the above-mentioned survival rates are for persons treated with surgery and/or currently available cancer chemotherapeutic agents [1,2]. A family of peptides referred to as atrial natriuretic peptides (ANPs) are synthesized within the heart and stored in the atrial myocyte as prohormones for rapid release in response to stimuli [3,4]. The ANP gene synthesizes a 126 amino acid (a.a.) prohormone, which contains four peptide hormones consisting of a.a. 1–30 (i.e. long-acting natri- uretic peptide, LANP), a.a. 31–67 (vessel dilator), a.a. 79–98 (kaliuretic peptide) and atrial natriuretic peptide (ANP, a.a. 99–126 of this prohormone) [3 – 5] (Fig. 1). Known biologic properties of these four peptide hormones include blood pressure lowering, diuresis, enhanced sodium and/or potassium excretion when infused into healthy animals [6–15] and humans [16–20]. One of these peptide hormones, i.e. atrial natriuretic peptide, has been investigated for growth regulatory Departments of Internal Medicine (D. L. Vesely, L. C. Clark, A. H. Garces, J. Soto), Biochemistry and Molecular Biology (Q. W. McAfee, W. R. Gower Jr), and Physiology and Biophysics (D. L. Vesely, W. R. Gower Jr), University of South Florida Cardiac Hormone Center; James A. Haley Veterans Medical Center (D. L. Vesely, L. C. Clark, A. H. Garces, Q. W. McAfee, J. Soto, W. R. Gower Jr), Tampa, FL, USA. Correspondence to: David L. Vesely, Professor of Medicine, Physiology & Biophysics, Director, USF Cardiac Hormone Center, 13000 Bruce B. Downs Blvd., Tampa, FL 33612, USA. Tel.: (813) 972–7624; fax: (813) 972 7623; e-mail: david.vesely@med.va.gov Received 2 July 2004; accepted 16 August 2004