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Regulatory and antiproliferative effects ofN-alkylated polyamine analogues in human and hamster pancreatic adenocarcinoma cell lines

  • Original Articles
  • Polyamine Analogues, Pancreatic Adenocarcinoma, Polyamine Biosynthesis
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Summary

N-Alkylated polyamine analogues have been shown to exert antiproliferative effects in several tumor models, with the bis-ethyl derivatives exerting the greatest suppression of polyamines by virtue of down-regulation of the polyamine biosynthetic enzymes. Pancreatic adenocarcinoma presents a challenge both clinically and experimentally due to its inherent resistance to conventional therapy, which results in its having the worst 5-year survival rate of all cancers. We have previously shown thatN 1,N 12-bis(ethyl)spermine (BESPM) is much more potent than the polyamine enzyme inhibitor α-difluoromethylornithine (DFMO) against pancreatic adenocarcinoma cell lines. In the present study, we compared the biochemical and antiproliferative effects of twoN-alkylated polyamine analogues,N 1,N 14-bis(ethyl)homospermine (BEHSPM) andN 1,N 11-bis(ethyl)norspermine (BENSPM) in two human pancreatic ductal adenocarcinoma cell lines, PANC-1 (poorly differentiated) and BxPC-3 (moderately well-differentiated), and in the WD PaCa (well-differentiated ductal) hamster cell line. BENSPM displayed greater antiproliferative activity in the human pancreatic cancer cell lines, whereas BEHSPM was more potent in the hamster cell line. Both BEHSPM and BENSPM suppress the activity of the major biosynthetic enzymes ornithine decarboxylase andS-adenosylmethionine decarboxylase. However, the induction of polyamine depletion in the human cell lines was only modest for BENSPM and minimal for BEHSPM, which suggests that the substantial antiproliferative activity of these analogues may result from mechanisms other than polyamine depletion. The somewhat greater polyamine depletion seen following treatment with BENSPM is thought to result from its striking induction of spermidine/spermineN 1-acetyltransferase. The biochemical and antiproliferative activity of BENSPM makes it an attractive agent for further preclinical and clinical development, especially in pancreatic cancer.

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Authors and Affiliations

  1. Department of Medicine, Medical College of Georgia and Augusta VA Medical Center, 30910, Augusta, GA, USA

    Barbara K. Chang (Associate Chief Staff/Education (141-U) & Yayun Liang

  2. Grace Cancer Drug Center, Roswell Park Cancer Institute, 14263, Buffalo, NY, USA

    Carl W. Porter & Paul R. Libby

  3. Department of Medicinal Chemistry, J. Hillis Miller Health Center, University of Florida, 32610, Gainesville, FL, USA

    Raymond J. Bergeron & J. R. Timothy Vinson

Authors
  1. Barbara K. Chang
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  2. Raymond J. Bergeron
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  3. Carl W. Porter
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  4. J. R. Timothy Vinson
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  5. Yayun Liang
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  6. Paul R. Libby
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Additional information

This investigation was supported by grant CH-468 from the American Cancer Society, by grant CA-37606 from the National Cancer Institute, Department of Health and Human Services, and by the Department of Veterans Affairs Medical Research Service

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Chang, B.K., Bergeron, R.J., Porter, C.W. et al. Regulatory and antiproliferative effects ofN-alkylated polyamine analogues in human and hamster pancreatic adenocarcinoma cell lines. Cancer Chemother. Pharmacol. 30, 183–188 (1992). https://doi.org/10.1007/BF00686309

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  • DOI: https://doi.org/10.1007/BF00686309

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