Multidrug resistance in pediatric malignancies.

PURPOSE

Increased expression of P-glycoprotein is an important cause of multidrug resistance in tumor cell lines in vitro. Whether this mechanism is equally relevant as a cause of clinical chemoresistance has not been established and is currently being investigated. This review has examined the immunohistochemical and molecular biologic tools suitable for assessing P-glycoprotein expression in patient samples and methodologic issues important for evaluating the results of clinical studies. Current evidence that supports a role for P-glycoprotein in limiting the efficacy of cancer chemotherapy has been reviewed.

DESIGN

Malignancies that have been successfully treated by chemotherapeutic substrates of P-glycoprotein, in which a proportion of patients still fail therapy, may be the most useful models for determining whether this drug efflux transporter is a clinically relevant cause of chemoresistance.

RESULTS

Studies of acute myelogenous leukemia, lymphoma, and myeloma in adults have so far provided the best evidence for a relevant role for P-glycoprotein as a cause of clinical multidrug resistance. A similar strong association has been observed between the expression of P-glycoprotein and outcome of treatment in certain malignancies in children, such as neuroblastoma, rhabdomyosarcoma, and acute lymphoblastic leukemia. Some apparent controversies related to this issue of clinical relevance may be explained by the differences in P-glycoprotein detection techniques, methodology, and experimental designs used in different studies. Because several clinical trials have already been initiated to determine whether pharmacologic chemosensitization improves the outcome of chemotherapy in certain malignancies, the successful verification of multidrug resistance limiting the cure rates of these tumors becomes a more critical issue, and identification of those patients with lower levels of P-glycoprotein expression early in the course of their disease, when they are most likely to benefit from multidrug resistance reversal, has assumed an even greater relevance.

CONCLUSION

The clinical relevance of the multidrug resistance P-glycoprotein may ultimately be confirmed by the successful prevention of chemotherapy failure by chemosensitizers that specifically reverse this drug efflux mechanism.