Abstract | 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: 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:
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Authors | Amy Hacker, Laurence J Marton, Michelle Sobolewski, Robert A Casero Jr |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 63
Issue 1
Pg. 45-53
(Dec 2008)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 18301893
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Animals
- Carcinoma, Non-Small-Cell Lung
(drug therapy, pathology)
- Carcinoma, Small Cell
(drug therapy, pathology)
- Cell Line, Tumor
(drug effects)
- Female
- Humans
- In Vitro Techniques
- Lung Neoplasms
(drug therapy, pathology)
- Mice
- Mice, Nude
- Molecular Conformation
- Polyamines
(chemistry, pharmacology, therapeutic use)
- Random Allocation
- Structure-Activity Relationship
- Xenograft Model Antitumor Assays
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