The holy grail of anticancer therapy is to deliver the cytotoxic agent to the cancer cell selectively and minimise the exposure to normal cells. Today there are several methods of targeting drugs to the appropriate site but many, such as monoclonal antibodies, are expensive and time consuming to develop. In recent years, extensive research has been devoted to the design of anticancer-polyamine conjugates since it was shown that rapidly proliferating and cancer cells display elevated intracellular polyamine content linked to increased activity of a specific polyamine transport system (PTS).1 Although, there is limited molecular knowledge regarding the identity and protein components of the PTS found in animal cells, it is known that the PTS is able to transport large substituent groups attached to a polyamine backbone. A successful example of the application of this strategy is the design of F14512, an etoposide-spermine conjugate, currently undergoing phase I clinical trials.2 The spermine moiety of F14512 functions both as a target vector for etoposide and as a subsidiary DNA anchor, leading to a reinforced inhibition of topoisomerase II. Our concept was therefore to use endogenous transport pathways that are up-regulated naturally in cancer cells to deliver novel cytotoxic intercalating agents3 more effectively to these cells and to assess the efficacy of these agents in terms of cytotoxicity and epigenetic changes. Different polyamine chains have been used to make hybrid drug molecules or conjugates in order to improve both the cellular import and the affinity for DNA. This study should help to better characterise the PTS and identify the optimal structural requirements for polyamine binding to the transporter.

Developing novel polyamine conjugates for selective anticancer therapy

MINARINI, ANNA
2014

Abstract

The holy grail of anticancer therapy is to deliver the cytotoxic agent to the cancer cell selectively and minimise the exposure to normal cells. Today there are several methods of targeting drugs to the appropriate site but many, such as monoclonal antibodies, are expensive and time consuming to develop. In recent years, extensive research has been devoted to the design of anticancer-polyamine conjugates since it was shown that rapidly proliferating and cancer cells display elevated intracellular polyamine content linked to increased activity of a specific polyamine transport system (PTS).1 Although, there is limited molecular knowledge regarding the identity and protein components of the PTS found in animal cells, it is known that the PTS is able to transport large substituent groups attached to a polyamine backbone. A successful example of the application of this strategy is the design of F14512, an etoposide-spermine conjugate, currently undergoing phase I clinical trials.2 The spermine moiety of F14512 functions both as a target vector for etoposide and as a subsidiary DNA anchor, leading to a reinforced inhibition of topoisomerase II. Our concept was therefore to use endogenous transport pathways that are up-regulated naturally in cancer cells to deliver novel cytotoxic intercalating agents3 more effectively to these cells and to assess the efficacy of these agents in terms of cytotoxicity and epigenetic changes. Different polyamine chains have been used to make hybrid drug molecules or conjugates in order to improve both the cellular import and the affinity for DNA. This study should help to better characterise the PTS and identify the optimal structural requirements for polyamine binding to the transporter.
2014
XXV Congresso Nazionale Società Chimica Italiana-Atti del Convegno
301
301
Anna, Minarini
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/521771
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