Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sarcomas of childhood rank fifth in incidence of malignant tumors in children younger than 15 years. Among the soft tissue sarcomas, approximately 50% are rhabdomyosarcomas. The remainder represent a heterogeneous group of diverse sarcomas which are not unique to children and include fibrosarcoma, synoviosarcoma, malignant fibrous histiocytoma, malignant schwannoma, angiosarcoma, leiomyosarcoma, and others. The most common bone cancers in childhood are osteosarcoma and Ewing's sarcoma. Although a multidisciplinary approach utilizing surgery, irradiation, and combination chemotherapy is routinely used in management of virtually all children with solid tumors, the value of adjuvant chemotherapy in select bone and rare soft tissue sarcomas is currently being tested. Multiagent chemotherapy including vincristine, dactinomycin, cyclophosphamide, and Adriamycin (doxorubicin) contribute to cure rates in 65% to 75% of children with localized rhabdomyosarcoma, Stages I to III, when combined with surgery and/or irradiation. Other drugs which hold promise include platinum, DTIC, methotrexate, and VP-16. The efficacy of similar drugs in the rarer pediatric soft tissue sarcomas other than rhabdomyosarcoma and its variants requires prospective randomized trials evaluating histologic grade, tumor size, and nodal status. It has been suggested that the high-grade sarcomas presenting with minimal tumor bulk are most sensitive to combined radiotherapy-chemotherapy, whereas the low-grade sarcomas are more resistant to such therapy. Tumor cell heterogeneity contributes to biologic diversity and response to treatment. Chemotherapy as adjuvant therapy to irradiation is currently recommended and utilized for Ewing's sarcoma with survival rates approaching 80%, and disease-free survival of approximately 75% for those with localized disease. Children with widespread and metastatic disease at presentation fare less well. Although multiple single agents exhibit response rates ranging from 40% to 60%, including cyclophosphamide, Adriamycin, dactinomycin, BCNU, mithramycin, and 5-fluorouracil, new and more effective agents are needed. Controversy regarding the value of multiagent chemotherapy in osteosarcoma has stimulated prospective randomized trials. Evaluation of local control rates as well as sites and occurrence of metastases are essential in assessing the contribution of aggressive combined modality therapy in the pediatric sarcomas. Emphasis on refinement of therapy in determining the risk/benefit ratio from adjuvant chemotherapy in pediatric sarcomas is mandatory. Enhancement of early local reactions is apparent when adjuvant chemotherapy is used with local radiotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The value of adjuvant chemotherapy in the management of sarcomas in children. 388 37

We investigated the long-term pulmonary sequelae of 38 children surviving 3 to 11.5 years (median 7 years) after high-dose chemotherapy (HDC) and autologous bone marrow transplantation (ABMT) without TBI. This cross-sectional study included patients with neuroblastoma (21), non-Hodgkin's lymphoma (7), Ewing's sarcoma (5), rhabdomyosarcoma (3), medulloblastoma (1) and ALL (1). They were asked and examined for clinical signs and underwent a physical examination with chest X-ray; 33/38 had pulmonary function tests (PFT) performed. No obstructive disease was found. Fifteen out of 32 evaluable PFT (47%) were abnormal with a pulmonary restrictive syndrome in 10, and borderline values in five patients. Four of these 15 patients were symptomatic with exertional dyspnea and two of four had abnormal chest X-rays. The etiology was mainly multifactorial, associating HDC with thoracic radiotherapy +/- scoliosis/kyphosis +/- previous thoracotomy +/- post-ABMT interstitial pneumonitis. Only 3/10 patients with a restrictive syndrome had HDC containing BCNU or busulfan as the only risk factor for lung disease. We conclude that the prevalence of late pulmonary sequelae after ABMT without TBI is moderate and rarely due to HDC alone, since most abnormal PFT can be explained by heavy pretreatment prior to ABMT. As symptoms are scarce even in advanced disease, repeated testing and very long-term follow-up are needed.
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PMID:Long-term pulmonary sequelae after autologous bone marrow transplantation in children without total body irradiation. 875 Feb 68

Medulloblastoma (D-341 MED) and rhabdomyosarcoma (TE-671) cell lines, which are resistant to either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or the combination of BCNU and O6-benzylguanine (O6-BG), were generated by serial escalation of BCNU. The activities of O6-alkylguanine-DNA alkyltransferase (AGT), glutathione-S-transferase (GST), and total glutathione (GSH) of the parental, BCNU-resistant (BR), and BCNU + O6-BG-resistant (OBR) cells were measured. No significant differences in GST activity or total GSH were seen between the parental, BR, and OBR cells of both TE-671 and D-341 MED. The AGT activities of D-341 MED (BR) and TE-671 (BR) were twice those of D-341 MED and TE-671, respectively, confirming the importance of this enzyme for BCNU resistance. The D-341 MED (OBR) cells did not exhibit any AGT activity, suggesting that another mechanism must play a role in the drug resistance. Fewer DNA interstrand cross-links (ICLs) were observed in D-341 MED (OBR) than in D-341 MED after 8 h BCNU (100-400 microM) treatment. However, the amounts of DNA ICLs observed in D-341 MED and D-341 MED (OBR) were stable after 24 h. Microarray analysis showed the increased expressions of several metallothionein genes and down-regulation of several proapoptotic genes. The AGT activity of TE-671 (OBR) was 223 fmol/mg when the cells were grown in 10 microM O6-BG and decreased to about half this value when the O6-BG concentration was increased 60 microM. The AGT cDNA of TE-671 (OBR) cells was cloned and found to contain a G-to-T transversion at codon 156, resulting in conversion of glycine to cysteine (G156C). In vitro mutagenesis has shown that the G156C AGT mutant is resistant to inactivation by O6-BG. Thus, the selection of a mutant AGT with decreased sensitivity to O6-BG is a significant contributing factor to BCNU + O6-BG resistance.
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PMID:Mechanisms of resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea in human medulloblastoma and rhabdomyosarcoma. 1247 69

The chemotherapeutic activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) may be improved by the addition of O6-benzylguanine (O6-BG). The reaction of O6-BG with O6-alkylguanine-DNA alkyltransferase (AGT) prevents the repair of O6-chloroethyl lesions caused by BCNU. In clinics, the combination of O6-BG and BCNU is now being tested for the treatment of brain tumors. However, the effectiveness of this drug regimen may be limited by drug resistance acquired during treatment. To understand the possible mechanisms of resistance of brain tumor cells to the O6-BG/BCNU combination, we generated medulloblastoma cell lines (D283 MED, D341 MED, and Daoy) resistant to the combination of O6-BG and BCNU [O6-BG/BCNU resistant (OBR)]. DNA sequencing showed that all of the parent cell lines express wild-type AGTs, whereas every OBR cell line exhibited mutations that potentially affected the binding of O6-BG to the protein as evidenced previously by in vitro mutagenesis and structural studies of AGT. The D283 MED (OBR), Daoy (OBR), and D341 MED (OBR) cell lines expressed G156C, Y114F, and K165T AGT mutations, respectively. We reported previously that rhabdomyosarcoma TE-671 (OBR) also expresses a G156C mutation. These data suggest that the clonal selection of AGT mutants during treatment with O6-BG plus an alkylator may produce resistance to this intervention in clinical settings.
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PMID:Brain tumor cell lines resistant to O6-benzylguanine/1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy have O6-alkylguanine-DNA alkyltransferase mutations. 1536 7