Abstract
This study evaluated the in vitro effect of L-canavanine on cell cycle progression in the two human pancreatic cancer cells lines PANC-1 and MIA PaCa-2. After 72 h of exposure to L-canavanine, the percentage of cells in the radiosensitive G2/M phase of the cell cycle increased 6-fold in PANC-1 cells and 4-fold in MIA PaCa-2 cells, when compared to untreated cells. The capacity of L-canavanine to redistribute cells into the G2/M phase of the cell cycle was both concentration-and time-dependent. Since many drugs that cause cells to accumulate in the G2/M phase of the cell cycle are effective radiosensitization agents, the potential of L-canavanine to synergistically enhance the effects of ionizing radiation also was evaluated. The interaction between these treatment modalities was quantified using the median-effect equation and combination index analysis. LCanavanine was found to be synergistic with radiation when either PANC-1 or MIA PaCa-2 cells were exposed to L-canavanine for 72 h prior to irradiation. These results suggest that L-canavanine in combination with radiation may have clinical potential in the treatment of pancreatic cancer. (Mol Cell Biochem 244: 37-43, 2003)
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References
Greenlee RT, Hill-Harmon MB, Murray T, Thun M: Cancer statistics, 2001. CA Cancer J Clin 51: 15–39, 2001
Warshaw AL, Fernandez-del Castillo C: Pancreatic carcinoma. N Engl J Med 326: 455–465, 1992
Rosenthal GA: The biological effects and mode of action of L-canavanine, a structural analogue of L-arginine. Q Rev Biol 52: 155–178, 1977
Thomas DA, Rosenthal GA, Gold DV, Dickey K: Growth inhibition of a rat colon tumor by L-canavanine. Cancer Res 46: 2898–2903, 1986
Green MH, Brooks TL, Mendelsohn J, Howell SB: Antitumor activity of L-canavanine against L1210 murine leukemia. Cancer Res 40: 535–537, 1980
Naha PM: An experimental model for selective inhibition of proliferating cells by chemotherapeutic agents. Cell Biol Int Rep 4: 829–839, 1980
Naha PM, Silcock JM, Fellows L: Reappraisal of L-canavanine as an anti-tumour agent. Cell Biol Int Rep 4: 155–166, 1980
Crooks PA, Rosenthal GA: Use of L-canavanine as a therapeutic agent for the treatment of pancreatic cancer. U.S. Patent 5,552,440. September 3, 1996
Thomas DA, Rosenthal GA: Toxicity and pharmacokinetics of the non-protein amino acid L-canavanine in the rat. Toxicol Appl Pharmacol 91: 395–405, 1987
Rosenthal GA, Dahlman DL: L-Canavanine and protein synthesis in the tobacco hornworm Manduca sexta. Proc Natl Acad Sci USA 83: 14–18, 1986
Rosenthal GA, Lambert J, Hoffmann D: Canavanine incorporation into the antibacterial proteins of the fly, Phormia terranovae (Diptera), and its effect on biological activity. J Biol Chem 264: 9768-9771, 1989
Rosenthal GA, Reichhart JM, Hoffmann JA: L-Canavanine incorporation into vitellogenin and macromolecular conformation. J Biol Chem 264: 13693–13696, 1989
Mattei E, Damasi D, Mileo AM, Delpino A, Ferrini U: Stress response, survival and enhancement of heat sensitivity in a human melanoma cell line treated with L-canavanine. Anticancer Res 12: 757–762, 1992
Laszlo A, Li GC: Effect of amino acid analogs on the development of thermotolerance and on thermotolerant cells. J Cell Physiol 154: 419–432, 1993
Ackerman WW, Cox DC, Dinka S: Control of histones and DNA synthesis with canavanine, puromycin, and polio virus. Biochem Biophys Res Commun 19: 745–750, 1965
Hare JD: Reversible inhibition of DNA synthesis by the arginine analog canavanine in hamster and mouse cells in vitro. Exptl Cell Res 58: 170–174, 1969
Schactele CF, Rogers P: Canavanine death in Escherichia coll. J Mol Biol 34: 474–489, 1965
Amorino GP, Freeman ML, Choy H: Enhancement of radiation effects in vitro by the estrogen metabolite 2-methoxyestradiol. Radiat Res 153: 384–391, 2000
Buolamwini JK: Cell cycle molecular targets in novel anticancer drug discovery. Curr Pharm Des 6: 379–392, 2000
Choy H, Rodriguez FF, Koester S, Hilsenbeck S, Von Hoff DD: Investigation of taxol as a potential radiation sensitizer. Cancer 71: 3774–3778, 1993
Bodner WR, Hilaris BS, Mastoras DA: Radiation therapy in pancreatic cancer: Current practice and future trends. J Clin Gastroenterol 30: 230–233, 2000
Green MH, Ward JF: Enhancement of human tumor cell killing by Lcanavanine in combination with y-radiation. Cancer Res 40: 4180–4182, 1983
Rosenthal GA: Preparation and colorimetric analysis of L-canavanine. Anal Biochem 77: 147–151, 1977
Rosenthal GA: The preparation and colorimetric analysis of L-canaline. Anal Biochem 51: 354–361, 1973
Bence AK, Crooks PA: Synthesis of L-indospicine. Syn Commun 32: 2075–2082, 2002
Cory AH, Owen TC, Barltrop JA, Cory JG: Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun 3: 207–212, 1991
Chou TC: Derivation and properties of Michaelis-Menten type and Hill type equations for reference ligands. J Theor Biol 59: 253–276, 1976
Chou TC, Talalay P: Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27–55, 1984
Merlin JL: Concepts of synergism and antagonism. Anticancer Res 14: 2315–2319, 1994
Ding Y, Matsukawa Y, Ohtani Fujita N, Kato D, Dao S, Fujii T, Naito Y, Yoshikawa T, Sakai T, Rosenthal GA: Growth inhibition of A549 human lung adenocarcinoma cells by L-canavanine is associated with p21/WAF1 induction. Jpn J Cancer Res 90: 69–74, 1999
Gu Y, Turck CW, Morgan DO: Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 366: 707–710, 1993
Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE: p53 mutations in pancreatic carcinoma and evidence of corn-mon involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 54: 3025–3033, 1994
Bouvet M, Bold RJ, Lee J, Evans DB, Abbruzzese JL, Chiao PJ, McConkey DJ, Chandra J, Chada S, Fang B, Roth JA: Adenovirusmediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer. Ann Surg Oncol 5: 681–688, 1998
Mogaki M, Hirota M, Chaney WG, Pour PM: Comparison of p53 protein expression and cellular localization in human and hamster pancreatic cancer cell lines. Carcinogenesis 14: 2589–2594, 1993
Wang SR, Su HL, Chiu CC, Huang MH, Tsai CY, Tsai JJ, Yu CL: Alteration of intracellular DNA and RNA patterns by liver arginase studied with flow cytometry. Chung Hua I Hsueh Tsa Chih (Taipei) 50: 267–272, 1992
Schmidlin A, Wiesinger H: Transport of L-arginine in cultured glial cells. Glia 11: 262–268, 1994
Rosenthal GA, Harper L: L-Homoarginine studies provide insight into the antimetabolic properties of L-canavanine. Insect Biochem Mol Biol 26: 389–394, 1996
Swaffar DS, Ang CY: Growth inhibitory effect of L-canavanine against MIA PaCa-2 pancreatic cancer cells is not due to conversion to its toxic metabolite canaline. Anticancer Drugs 10: 113–118, 1999
Terasima T, Tolmach LJ: X-ray sensitivity and DNA synthesis in synchronous populations of HeLa Cells. Science 140: 490–492, 1963
Sinclair WK, Morton RA: X-ray sensitivity during the cell generation cycle of cultured Chinese hamster cells. Radiat Res 29: 450–474, 1966
Brown KD, Lataxes TA, Shangary S, Mannino JL, Giardina JF, Chen J, Baskaran R: Ionizing radiation exposure results in up-regulation of Ku70 via a p53/ataxia-telangiectasia-mutated protein-dependent mechanism. J Biol Chem 275: 6651–6656, 2000
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Bence, A.K., Adams, V.R., Crooks, P.A. (2003). L-Canavanine as a radiosensitization agent for human pancreatic cancer cells. In: Clark, J.F. (eds) Guanidino Compounds in Biology and Medicine. Molecular and Cellular Biochemistry, vol 40. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0247-0_5
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DOI: https://doi.org/10.1007/978-1-4615-0247-0_5
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