George Haddad

P-Glycoprotein Expression as a Predictor of the Outcome of Therapy for Neuroblastoma

BACKGROUND AND METHODS Multidrug resistance in chemotherapy for cancer is characterized by increased genetic expression of P-glycoprotein, which acts as an ATP-dependent drug-efflux pump. To determine whether P-glycoprotein levels are of prognostic value in such cases, we measured these levels immunohistochemically in a retrospective study of sequential tumor samples from 67 children with neuroblastoma. RESULTS P-glycoprotein was not detected in pretreatment samples from either of the 2 patients with Stage I disease, any of the 21 with Stage II disease, or any of the 8 with Stage IVS disease, but it was detected in the samples from 1 of the 17 patients with Stage III disease (6 percent) and 12 of the 19 with Stage IV disease (63 percent). Of the 44 patients with nonlocalized neuroblastoma (Stage III, IVS, or IV), 26 of the 31 who were negative for P-glycoprotein had a complete response to primary treatment, as compared with 6 of the 13 who were positive for P-glycoprotein (84 percent vs. 46 percent, P = 0.0232 by Fishers exact test). Log-rank analysis of outcome, with simultaneous stratification according to tumor stage and age, showed that the group that was negative for P-glycoprotein had significantly longer relapse-free survival (P = 0.0011) and overall survival (P = 0.0373) than the group that was positive. CONCLUSIONS Expression of P-glycoprotein before treatment may predict the success or failure of therapy for nonlocalized neuroblastoma. Neuroblastoma may be a promising tumor to treat with anticancer drug therapy combined with a chemosensitizing agent capable of reversing P-glycoprotein-mediated multidrug resistance.

Multidrug-resistant Phenotype in Retinoblastoma Correlates with P-glycoprotein Expression

Chemotherapy plays an important role in therapy for patients with extraocular and metastatic retinoblastoma. The authors used chemotherapy for management of selected patients with uncontrolled intraocular tumors or tumors larger and more posteriorly located than those conventionally treated with local cryotherapy or photocoagulation. Rapid regrowth of some tumors after an initial excellent chemotherapy response led us to investigate the hypothesis that failure of treatment is caused by P-glycoprotein-related multidrug resistance. By using a sensitive immunoperoxidase method, increased P-glycoprotein was detected in five multidrug-resistant and two selectively plant alkaloid-resistant retinoblastoma cell lines and in the intraocular and metastatic tumors from which they were derived. In four chemotherapy-treated cases, increased P-glycoprotein in the tumor samples correlated with clinically relevant drug resistance. None of the four chemosensitive tumor cell lines had increased P-glycoprotein expression. Continuous surveillance of P-glycoprotein levels in metastatic retinoblastoma may be a useful guide to drug therapy.

Multidrug Resistance in Cancers of Childhood: Clinical Relevance and Circumvention

Publisher Summary The studies of the expression of P-glycoprotein in rhabdomyosarcoma and undifferentiated sarcoma of childhood, neuroblastoma, retinoblastoma, and most recently osteogenic sarcoma have shown that an increase in the protein is present in a considerable proportion of tumors at diagnosis prior to treatment. The incidence of increased P-glycoprotein is as high as one-tenth that of all regional stage III neuroblastoma, one-quarter that of intraocular retinoblastoma, one-third of regional groups 2 and 3 rhabdomyosarcoma, and two-fifths that of nonmetastatic osteogenic sarcoma. The levels of P-glycoprotein are usually lower in the primary tumors at diagnosis compared with recurrent tumors at the primary sites and metastatic locations. As the expression of P-glycoprotein in the tumors of childhood is relatively low initially at diagnosis and only few tumor cells are positive, refined immunohistochemical assays with improved sensitivity have been developed as an approach toward circumventing low levels of expression and focal positivity resulting from tumor heterogeneity. In these tumors, there is a strong association between increased P-glycoprotein at diagnosis and poor responses to treatment, early relapses, and increased mortality. The chapter explores the possibility of future clinical opportunities for improving the therapeutic outcome of nonresponsive adult and childhood malignancies that lie in the development of more effective chemotherapy, better methods for detection of non-P-glycoprotein-related mechanisms of drug resistance, more potent chemosensitizers, and improved methods that specifically target the reversal of the various mechanisms of drug resistance.