PURPOSE: Polyamines are essential for normal growth; however, the requirement for, and the metabolism of, polyamines are frequently dysregulated in cancer. Polyamine analogues have demonstrated promising preclinical results in multiple model systems of cancer, but their clinical utility has been limited by apparent toxicity. A representative compound of a new generation of short chain, conformationally restricted polyamine analogues, CGC-11047 has been synthesized and ongoing phase I clinical trials indicate it to be well tolerated at weekly doses of 610 mg (dose escalation is still in progress). Therefore, studies were designed to gain a better understanding of its effects on cellular polyamine biochemistry and efficacy in the treatment of human lung cancer models in vitro and in vivo. METHODS: Human lung cancers cell lines representing non-small cell and small cell lung cancers were investigated for their growth and biochemical response to CGC-11047. Effects of in vitro treatment with CGC-11047 on cell growth, the activity of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC), and the expression and activity of the polyamine catabolic enzymes spermidine/spermine N(1)-acetyltransferase (SSAT) and spermine oxides (SMO) were measured. Additionally, the overall effects on intracellular polyamine pools were monitored. Finally, the in vivo efficacy of CGC-11047 in the treatment of a nude mouse model of human non-small cell lung cancer was evaluated. RESULTS: CGC-11047 effectively inhibited the growth of both small cell and non-small cell lung cancer cells in vitro. The greatest biochemical effects were observed in the non-small cell lung cancer cells where in addition to a profound down regulation of ODC activity, there was a significant increase in polyamine catabolism leading to a greater degree of polyamine pool depletion and greater accumulation of CGC-11047 when compared with the changes observed for the small cell lines. Importantly, CGC-11047 was found to be highly significant (P < 0.0001) in delaying the progression of established tumors in an in vivo model of human non-small cell lung cancer. CONCLUSION: CGC-11047 represents a promising new polyamine analogue that warrants further preclinical and, potentially, clinical evaluation in lung cancer.
PURPOSE:Polyamines are essential for normal growth; however, the requirement for, and the metabolism of, polyamines are frequently dysregulated in cancer. Polyamine analogues have demonstrated promising preclinical results in multiple model systems of cancer, but their clinical utility has been limited by apparent toxicity. A representative compound of a new generation of short chain, conformationally restricted polyamine analogues, CGC-11047 has been synthesized and ongoing phase I clinical trials indicate it to be well tolerated at weekly doses of 610 mg (dose escalation is still in progress). Therefore, studies were designed to gain a better understanding of its effects on cellular polyamine biochemistry and efficacy in the treatment of humanlung cancer models in vitro and in vivo. METHODS:Humanlung cancers cell lines representing non-small cell and small cell lung cancers were investigated for their growth and biochemical response to CGC-11047. Effects of in vitro treatment with CGC-11047 on cell growth, the activity of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC), and the expression and activity of the polyamine catabolic enzymes spermidine/spermine N(1)-acetyltransferase (SSAT) and spermine oxides (SMO) were measured. Additionally, the overall effects on intracellular polyamine pools were monitored. Finally, the in vivo efficacy of CGC-11047 in the treatment of a nude mouse model of humannon-small cell lung cancer was evaluated. RESULTS:CGC-11047 effectively inhibited the growth of both small cell and non-small cell lung cancer cells in vitro. The greatest biochemical effects were observed in the non-small cell lung cancer cells where in addition to a profound down regulation of ODC activity, there was a significant increase in polyamine catabolism leading to a greater degree of polyamine pool depletion and greater accumulation of CGC-11047 when compared with the changes observed for the small cell lines. Importantly, CGC-11047 was found to be highly significant (P < 0.0001) in delaying the progression of established tumors in an in vivo model of humannon-small cell lung cancer. CONCLUSION:CGC-11047 represents a promising new polyamine analogue that warrants further preclinical and, potentially, clinical evaluation in lung cancer.
Authors: P J Creaven; R Perez; L Pendyala; N J Meropol; G Loewen; E Levine; E Berghorn; D Raghavan Journal: Invest New Drugs Date: 1997 Impact factor: 3.850
Authors: John L A Mitchell; Carrie L Simkus; Thynn K Thane; Phil Tokarz; Michelle M Bonar; Benjamin Frydman; Aldonia L Valasinas; Venodhar K Reddy; Laurence J Marton Journal: Biochem J Date: 2004-12-01 Impact factor: 3.857
Authors: Malcolm A Smith; John M Maris; Richard Lock; E Anders Kolb; Richard Gorlick; Stephen T Keir; Hernan Carol; Christopher L Morton; C Patrick Reynolds; Min H Kang; Peter J Houghton Journal: Pediatr Blood Cancer Date: 2011-02-25 Impact factor: 3.167
Authors: Tracy Murray Stewart; Apurva A Desai; Michael L Fitzgerald; Laurence J Marton; Robert A Casero Journal: Cancer Chemother Pharmacol Date: 2020-05-23 Impact factor: 3.333
Authors: M D Thulani Senanayake; Hemali Amunugama; Tracey D Boncher; Robert A Casero; Patrick M Woster Journal: Essays Biochem Date: 2009-11-04 Impact factor: 8.000
Authors: Natalia A Ignatenko; Hagit F Yerushalmi; Ritu Pandey; Karen L Kachel; David E Stringer; Laurence J Marton; Eugene W Gerner Journal: Cancer Genomics Proteomics Date: 2009 May-Jun Impact factor: 4.069
Authors: Wen-Lin Kuo; Debopriya Das; Safiyyah Ziyad; Sanchita Bhattacharya; William J Gibb; Laura M Heiser; Anguraj Sadanandam; Gerald V Fontenay; Zhi Hu; Nicholas J Wang; Nora Bayani; Heidi S Feiler; Richard M Neve; Andrew J Wyrobek; Paul T Spellman; Laurence J Marton; Joe W Gray Journal: BMC Med Date: 2009-12-14 Impact factor: 8.775