Multidrug resistance in pediatric oncology

Abstract

Cancer survival among children and adolescents has improved markedly due to evolution of multimodal treatment that incorporates combination chemotherapy, radiation therapy and/or surgery. However, 20-30% of children with malignancies will succumb to their disease or complications associated with their disease or treatment. A major limiting factor to improvement in survival among these patients is the occurrence of intrinsic and/or acquired resistance to our treatment interventions, chemotherapy and radiotherapy. Among these mechanisms, multidrug resistance, the focus of this review, is a well-documented phenomenon whose biochemistry, pharmacology and molecular biology has been extensively studied. A role for multidrug resistance in chemoresistance and therapeutic failure in childhood malignancies is suggested by the observation of clinical resistance to treatment regimes containing agents that are known substrates of multidrug resistance mechanisms. With the current results from studies in rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, leukemia and retinoblastoma, the role of multidrug resistance is still unclear. Earlier studies attempted to define a role for P-glycoprotein-mediated multidrug resistance; however, a limited number of reports suggest that the multidrug-associated resistance protein may play an active role in neuroblastoma. Further studies will be necessary using standardized and uniform approaches for the analyses of these mechanisms. Clinical trials directed toward reversal of multidrug resistance are premature since the exact role of P-glycoprotein is controversial in pediatric malignancies, the role of other mechanisms of multidrug resistance must be assessed and selective inhibitors of multidrug resistance have yet to be developed.

Ornithine Decarboxylase Inhibition by α-Difluoromethylornithine Activates Opposing Signaling Pathways via Phosphorylation of Both Akt/Protein Kinase B and p27Kip1 in Neuroblastoma

“…NB patients diagnosed under the age of 1 year often experience complete regression of tumors while older patients often struggle with more advanced stages of the disease, malignant progression, and poor prognosis partly due to the emergence of multi-drug resistance (1-3). The mechanisms that control the progression or regression of NB tumors have yet to be elucidated and thus present a difficult challenge for the treatment of this disease.…”

Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia

“…8 Studies of the prognostic significance of P-gp expression in pediatric cancers remain controversial. [9][10][11][12] Some show that its expression might be related to poor survival or risk of relapse, whereas others show no prognostic significance. [13][14][15][16][17][18][19][20] Studies using cyclosporins to modulate MDR [21][22][23][24][25] have been performed in children with AML or retinoblastoma.…”

Assessment of chemosensitivity in patients with osteogenic sarcoma using the doxorubicin binding assay

“…It is well known that patients with initial high chemosensitivity often acquire resistance to drugs during the course of treatment [16]. Chemotherapy eliminates the sensitive cells while allowing resistant cells to multiply and eventually metastasize.…”