Lonidamine (LND) 1, a drug currently used in the treatment of several neoplasia (i.e. lung, breast, prostate and brain). Its mechanism of action does not affect the protein or nucleic acids synthesis but LND acts reducing the oxygen consumption, and reducing glucose utilization of neoplastic cells by inhibition of mitochondria-bound glycolitic enzyme hexokinase that is usually absent in normal cells. Thus mitochondria represents the intracellular target of LND. Due to its original mechanism of action, LND is devoid of the usual side effects induced by antiproliferative agents and no serious adverse reactions have been reported even over a long-term treatment period. This gives to LND an added value as anticancer drug candidate.(1) However, pancreatic and hepatic toxicity were observed in dogs receiving LND by intravenous injection whereas oral administration of LND was devoid of such a toxicity in the same studies suggesting that the bioavailability of LND may be limited by its extremely low water solubility (17 mg/L).(2) The present study concerns potential LND prodrugs bearing high hydrophilic molecules such as sugars and polyalcohols conjugated to the carboxyl group of the molecule as an attempt to increase the water solubility of LND itself.
Polyhydroxylic Prodrugs of Lonidamine
GIORGIONI, Gianfabio;RUGGIERI, Sabrina;CLAUDI, Francesco
2007-01-01
Abstract
Lonidamine (LND) 1, a drug currently used in the treatment of several neoplasia (i.e. lung, breast, prostate and brain). Its mechanism of action does not affect the protein or nucleic acids synthesis but LND acts reducing the oxygen consumption, and reducing glucose utilization of neoplastic cells by inhibition of mitochondria-bound glycolitic enzyme hexokinase that is usually absent in normal cells. Thus mitochondria represents the intracellular target of LND. Due to its original mechanism of action, LND is devoid of the usual side effects induced by antiproliferative agents and no serious adverse reactions have been reported even over a long-term treatment period. This gives to LND an added value as anticancer drug candidate.(1) However, pancreatic and hepatic toxicity were observed in dogs receiving LND by intravenous injection whereas oral administration of LND was devoid of such a toxicity in the same studies suggesting that the bioavailability of LND may be limited by its extremely low water solubility (17 mg/L).(2) The present study concerns potential LND prodrugs bearing high hydrophilic molecules such as sugars and polyalcohols conjugated to the carboxyl group of the molecule as an attempt to increase the water solubility of LND itself.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
