ABSTRACT
BACKGROUND: Many patients with retinoblastoma have a genetic predisposition to cancer and external beam radiation therapy and alkylating agent chemotherapy may increase their risk of secondary malignancy. Identification of effective chemotherapy agents for retinoblastoma that are not associated with an elevated risk of secondary malignancy would be beneficial. PROCEDURE: Twenty-six specimens of fresh retinoblastoma tumor cells were studied in vitro with a PT430 competitive displacement assay. Differential displacement of the PT430 by methotrexate and not trimetrexate was considered indicative of a defect in reduced folate carrier (RFC)-mediated transport. Elevations in the accumulation of PT430 were considered indicative of dihydrofolate reductase (DHFR) amplification. RESULTS: In 9 of the 26 (35%) samples, displacement by methotrexate was less than half the displacement by trimetrexate indicative of a defect in the RFC. In 5 of the 26 (19%) samples, trimetrexate did not displace the PT430. In 7 of 26 (27%) samples, the peak PT430 accumulation was suggestive of DHFR overexpression. Overall 9 of 26 (35%) samples had no evidence of a transport defect or DHFR overexpression and would be anticipated to be potentially sensitive to methotrexate. In 15 of the 26 (58%), no defects existed in trimetrexate displacement or DHFR overexpression and would be anticipated to be potentially sensitive to trimetrexate. CONCLUSION: These results would support consideration of a phase II study to determine the effectiveness of trimetrexate for recurrent intra-ocular retinoblastoma.
Subject(s)
Antimetabolites, Antineoplastic/metabolism , Folic Acid Antagonists/metabolism , Membrane Transport Proteins/metabolism , Methotrexate/pharmacology , Neoplasm Proteins/metabolism , Retinal Neoplasms/metabolism , Retinoblastoma/metabolism , Tetrahydrofolate Dehydrogenase/metabolism , Trimetrexate/pharmacology , Adolescent , Antimetabolites, Antineoplastic/pharmacology , Binding, Competitive , Biological Transport/genetics , Child , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Female , Folic Acid Antagonists/pharmacology , Humans , Infant , Male , Membrane Transport Proteins/genetics , Methotrexate/analogs & derivatives , Methotrexate/metabolism , Neoplasm Proteins/genetics , Neoplasms, Second Primary/chemically induced , Neoplasms, Second Primary/prevention & control , Reduced Folate Carrier Protein , Retinal Neoplasms/pathology , Retinoblastoma/pathology , Tetrahydrofolate Dehydrogenase/genetics , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/pathology , Uterine Cervical Dysplasia/metabolism , Uterine Cervical Dysplasia/pathologyABSTRACT
Dynamic enhanced magnetic resonance imaging has been used to assess tumor angiogenesis in osteosarcoma. Vascular endothelial growth factor has been shown to correlate with pulmonary metastasis and a poor prognosis in osteosarcoma. The purpose of this investigation was to determine whether vascular endothelial growth factor expression in osteosarcoma correlates with vascular permeability detected by dynamic enhanced magnetic resonance imaging and to explore the role of dynamic enhanced magnetic resonance imaging as a noninvasive means of assessing tumor angiogenic activity. Fifty-five osteosarcoma patients with osteosarcoma enrolled in a treatment protocol that included dynamic enhanced magnetic resonance imaging. In 15 patients, tumor tissues were available for vascular endothelial growth factor immunohistochemical studies. A two-compartment model used the exchange rate constants (kep) between the plasma and tumor compartments to quantify vascular permeability during dynamic magnetic resonance imaging studies. Immunohistochemical staining for vascular endothelial growth factor was graded according to the intensity and number of positively stained cells. Vascular endothelial growth factor-positive tumors showed higher mean vascular permeability when compared with vascular endothelial growth factor-negative tumors. Vascular permeability also correlated with increasing vascular endothelial growth factor expression. The preliminary results in this study show an association between vascular endothelial growth factor and dynamic MR signal enhancement in osteosarcoma. Dynamic enhanced magnetic resonance imaging should be investigated as a means to prognosticate osteosarcoma patients with osteosarcoma according to their tumor angiogenic activity.
