One of the problems with anticancer drugs is the lack of selectivity towards tumour cells. Ideally, the drugs should be delivered to the site of action where they will be effective against the tumour cells but have minimal toxicity towards normal cells. Polyamines (putrescine, spermidine and spermine) are ubiquitously expressed polycationic molecules which play an essential role in cell growth and proliferation. Rapidly proliferating and cancer cells display elevated intracellular polyamine content linked to increased activity of the polyamine transport system (PTS). The PTS is promiscuous and quite tolerant in that it is able to transport large substituent groups attached to a polyamine backbone. Polyamines are also positively charged and are known to interact with the phosphate groups of the DNA. Our hypothesis is therefore that by conjugating a polyamine tail to a toxic DNA intercalating moiety we can deliver the cytotoxicity more selectively to the cancer cells together with an improved interaction with DNA. This study aimed to determine cytotoxic characteristics of four naphthalene diimide-polyamine conjugates: CM3, CM32 and CM52 on human leukaemic and pancreatic cancer cells. The polyamine conjugates were compared to standard chemotherapeutic agents. Cytotoxicity was established by MTT assay and IC50 values determined. Indirect evidence for the conjugates utilising the PTS was obtained by stimulation of the PTS with DFMO pretreatment. The conjugates exhibited a range of toxicities within the low micromolar range. It is clear that the number and arrangement of amine groups within the polyamine tail affects conjugate toxicity and the uptake by the PTS.
Welsh, S., Li, H., Marchetti, C., Tumiatti, V., Minarini, A., Wallace, H. (2014). Preliminary evaluation of the cytotoxicity of naphthalene diimide-polyamine conjugates in human cancer cells. ELSEVIER IRELAND LTD [10.1016/j.toxlet.2014.06.888].
Preliminary evaluation of the cytotoxicity of naphthalene diimide-polyamine conjugates in human cancer cells
MARCHETTI, CHIARA;TUMIATTI, VINCENZO;MINARINI, ANNA;
2014
Abstract
One of the problems with anticancer drugs is the lack of selectivity towards tumour cells. Ideally, the drugs should be delivered to the site of action where they will be effective against the tumour cells but have minimal toxicity towards normal cells. Polyamines (putrescine, spermidine and spermine) are ubiquitously expressed polycationic molecules which play an essential role in cell growth and proliferation. Rapidly proliferating and cancer cells display elevated intracellular polyamine content linked to increased activity of the polyamine transport system (PTS). The PTS is promiscuous and quite tolerant in that it is able to transport large substituent groups attached to a polyamine backbone. Polyamines are also positively charged and are known to interact with the phosphate groups of the DNA. Our hypothesis is therefore that by conjugating a polyamine tail to a toxic DNA intercalating moiety we can deliver the cytotoxicity more selectively to the cancer cells together with an improved interaction with DNA. This study aimed to determine cytotoxic characteristics of four naphthalene diimide-polyamine conjugates: CM3, CM32 and CM52 on human leukaemic and pancreatic cancer cells. The polyamine conjugates were compared to standard chemotherapeutic agents. Cytotoxicity was established by MTT assay and IC50 values determined. Indirect evidence for the conjugates utilising the PTS was obtained by stimulation of the PTS with DFMO pretreatment. The conjugates exhibited a range of toxicities within the low micromolar range. It is clear that the number and arrangement of amine groups within the polyamine tail affects conjugate toxicity and the uptake by the PTS.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
