RESUMEN
p21(WAF1/Cip1) was initially identified as a cell cycle regulatory protein that can cause cell cycle arrest. It is induced by both p53-dependent and p53-independent mechanisms. This mini-review briefly discusses its currently known functions in apoptosis and drug sensitivity. As an inhibitor of cell proliferation, p21(WAF1/Cip1) plays an important role in drug-induced tumor suppression. Nevertheless, a number of recent studies have shown that p21(WAF1/Cip1) can assume both pro- or anti-apoptotic functions in response to anti-tumor agents depending on cell type and cellular context. This dual role of p21(WAF1/Cip1) in cancer cells complicates using p21(WAF1/Cip1) status to predict response to anti-tumor agents. However, it is possible to develop p21(WAF1/Cip1)-targeted reagents or p21(WAF1/Cip1) gene transfer techniques to have a beneficial effect within a well-defined therapeutic context. Better understanding of the roles of p21(WAF1/Cip1) in tumors should enable a more rational approach to anti-tumor drug design and therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular/fisiología , Proteínas de Ciclo Celular/farmacocinética , Ciclinas/fisiología , Ciclinas/farmacocinética , Resistencia a Antineoplásicos , Apoptosis/fisiología , Proteínas de Ciclo Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , Técnicas de Transferencia de Gen , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/fisiopatología , Resultado del TratamientoRESUMEN
The use of copper radioisotopes in imaging and therapy applications has created a greater need for bifunctional chelates (BFCs) for complexing copper radioisotopes to biomolecules. It has been demonstrated that the charge and lipophilicity of the Cu-BFC complex has a significant effect on the in vivo behavior of the radiolabeled Cu-BFC-biomolecule conjugate. To evaluate the effects of charge, stability, and macrocyclic backbone size on the biological behavior of 64Cu complexes, a series of macrocyclic 64Cu complexes have been prepared, and the biodistributions of these agents were evaluated in normal Sprague-Dawley rats. Two macrocyclic backbones, dodecane and tetradecane, were evaluated; cyclen, DOTA, and DO2A were dodecane backbone derivatives, and cyclam, TETA, and et-cyclam were tetradecane backbone derivatives. The biodistributions of the 64Cu-labeled complexes correlated with differences in the size of the macrocycle backbone and the formal charge of the complex. All compounds showed uptake and clearance through the liver and kidneys; however, the positively charged 64Cu complexes showed significantly higher uptake in both of these organs than did the negatively charged or neutral complexes. 64Cu-TETA, a negatively charged complex with the tetradecane backbone, had the most efficient clearance by 24 hours' postinjection. These data suggest that negatively charged complexes may have more favorable clearance properties when used as BFCs.