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Title of Journal: Amino Acids

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Abbravation: Amino Acids

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Springer Vienna

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DOI

10.1007/0-306-47186-8_9

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ISSN

1438-2199

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Distamycin A and derivatives as synergic drugs in

Authors: Gaetano Marverti Giambattista Guaitoli Alessio Ligabue Chiara Frassineti Maria Giuseppina Monti Paolo Lombardi Maria Paola Costi
Publish Date: 2011/08/04
Volume: 42, Issue: 2-3, Pages: 641-653
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Abstract

Acquired resistance to cisplatin cDDP is a multifactorial process that represents one of the main problems in ovarian cancer therapy Distamycin A is a minor groove DNA binder whose toxicity has limited its use and prompted the synthesis of derivatives such as NAX001 and NAX002 which have a carbamoyl moiety and different numbers of pyrrolamidine groups Their interaction with a BDNA model and with an extendedTATA box model PolydAT was investigated using isothermal titration calorimetry ITC to better understand their mechanism of interaction with DNA and therefore better explain their cellular effects Distamycin A interactions with Dickerson and PolydAT6 oligonucleotides show a different thermodynamic with respect to NAX002 The bulkier distamycin A analogue shows a non optimal binding to DNA due to its additional pyrrolamidine group Cellular assays performed on cDDPsensitive and resistant cells showed that these compounds distamycin A in particular affect the expression of folate cycle enzymes even at cellular level The optimal interaction of distamycin A with DNA may account for the downregulation of both dihydrofolate reductase DHFR and thymidylate synthase TS and the upregulation of spermidine/spermine N1acetyltransferase SSAT caused by this compound These effects seem differently modulated by the cDDPresistance phenotype NAX002 which presents a lower affinity to DNA and slightly affected these enzymes showed a synergic inhibition profile in combination with cDDP In addition their combination with cDDP or polyamine analogues increased cell sensitivity to the drugs suggesting that these interactions may have potential for development in the treatment of ovarian carcinoma

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