TY - JOUR
T1 - Retinoid related molecules an emerging class of apoptotic agents with promising therapeutic potential in oncology
T2 - Pharmacological activity and mechanisms of action
AU - Garattini, Enrico
AU - Gianni', Maurizio
AU - Terao, Mineko
PY - 2004
Y1 - 2004
N2 - Retinoic acid and derivatives (retinoids) exert their anti-neoplastic action through three different, though partially overlapping mechanisms: growth-inhibition, cyto-differentiation and apoptosis. Retinoid related molecules (RRMs) are a promising class of synthetic retinoic acid derivatives endowed with selective apoptotic activity on a large variety of leukemic and solid tumor cells. The in vitro apoptotic activity of RRMs translates into in vivo efficacy in a number of experimental models of neoplasia. The prototype of this novel family of cytotoxic agents is CD437, a conformation restricted retinoid originally developed as a selective RARγ agonist. A number of new RRM congeners, including ST1926, MM002, MM11453 and MX-3350-1, have been recently reported in the literature. Some of these compounds have a stronger apoptotic potential, a lower level of toxicity and a better pharmacokinetic profile than CD437. RRMs have a molecular mechanism of action that is entirely different from that of many other known chemotherapeutics. These compounds induce apoptosis in retinoic acid- and multi-drug-resistant neoplastic cells. The apoptotic process triggered by RRMs is independent of p53 activation and proceeds through a novel pathway in which the mitochondrion seems to play a pivotal role. RRMs show only very limited cross-resistance with other classes of chemotherapeutic agents and show synergistic interactions with a number of classical cyto-toxic agents. The article presents a critical overview of the current knowledge on the pharmacology of RRMs focussing on such issues as the spectrum of cytotoxic activity, the molecular mechanisms of action and the pre-clinical basis of clinical development.
AB - Retinoic acid and derivatives (retinoids) exert their anti-neoplastic action through three different, though partially overlapping mechanisms: growth-inhibition, cyto-differentiation and apoptosis. Retinoid related molecules (RRMs) are a promising class of synthetic retinoic acid derivatives endowed with selective apoptotic activity on a large variety of leukemic and solid tumor cells. The in vitro apoptotic activity of RRMs translates into in vivo efficacy in a number of experimental models of neoplasia. The prototype of this novel family of cytotoxic agents is CD437, a conformation restricted retinoid originally developed as a selective RARγ agonist. A number of new RRM congeners, including ST1926, MM002, MM11453 and MX-3350-1, have been recently reported in the literature. Some of these compounds have a stronger apoptotic potential, a lower level of toxicity and a better pharmacokinetic profile than CD437. RRMs have a molecular mechanism of action that is entirely different from that of many other known chemotherapeutics. These compounds induce apoptosis in retinoic acid- and multi-drug-resistant neoplastic cells. The apoptotic process triggered by RRMs is independent of p53 activation and proceeds through a novel pathway in which the mitochondrion seems to play a pivotal role. RRMs show only very limited cross-resistance with other classes of chemotherapeutic agents and show synergistic interactions with a number of classical cyto-toxic agents. The article presents a critical overview of the current knowledge on the pharmacology of RRMs focussing on such issues as the spectrum of cytotoxic activity, the molecular mechanisms of action and the pre-clinical basis of clinical development.
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U2 - 10.2174/1381612043453351
DO - 10.2174/1381612043453351
M3 - Article
C2 - 14965204
AN - SCOPUS:0742271644
VL - 10
SP - 433
EP - 448
JO - Current Pharmaceutical Design
JF - Current Pharmaceutical Design
SN - 1381-6128
IS - 4
ER -