Multidrug resistance is a significant obstacle to providing effective chemotherapy to many cancer patients, leading to failure of several medical treatments, with dramatic consequences for the patients. Resistance to chemotherapy is associated with the overexpression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapic agents from cancer cells. P-gp is a 170 Kd transmembrane glycoprotein, encoded by the multidrug resistance gene 1 (MDR1), which is expressed in many cancer cell lines and human tissues. Several reports describe the successful overcoming of drug resistance by inactivation of MDR1 function or expression, and, recently, an important role for cyclooxygenase-2 (COX-2) has been reported in modulating MDR1 function. Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid parafollicular C cells, which is highly resistant to chemotherapy, and, so far, nonsurgical approaches to MTC treatment have met with inconsistent results. Many other endocrine-related cancers (i.e. breast cancer), as well as endocrine gland cancers (i.e. adrenocortical cancer) may display chemoresistance or develop such phenotype after the first chemotherapy courses. The aim of the proposed research is to explore the possible pathways for overcoming multidrug resistance by treatment with compounds inhibiting COX-2 activity. It has been demonstrated that COX-2 activity dose-dependently induces P-gp function.
Finding a path to overcome chemoresistance
ZATELLI, Maria Chiara
2006
Abstract
Multidrug resistance is a significant obstacle to providing effective chemotherapy to many cancer patients, leading to failure of several medical treatments, with dramatic consequences for the patients. Resistance to chemotherapy is associated with the overexpression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapic agents from cancer cells. P-gp is a 170 Kd transmembrane glycoprotein, encoded by the multidrug resistance gene 1 (MDR1), which is expressed in many cancer cell lines and human tissues. Several reports describe the successful overcoming of drug resistance by inactivation of MDR1 function or expression, and, recently, an important role for cyclooxygenase-2 (COX-2) has been reported in modulating MDR1 function. Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid parafollicular C cells, which is highly resistant to chemotherapy, and, so far, nonsurgical approaches to MTC treatment have met with inconsistent results. Many other endocrine-related cancers (i.e. breast cancer), as well as endocrine gland cancers (i.e. adrenocortical cancer) may display chemoresistance or develop such phenotype after the first chemotherapy courses. The aim of the proposed research is to explore the possible pathways for overcoming multidrug resistance by treatment with compounds inhibiting COX-2 activity. It has been demonstrated that COX-2 activity dose-dependently induces P-gp function.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
