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

N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)-urea (LY186641), a novel anticancer compound, was evaluated against six lines of rhabdomyosarcoma xenografts, each of which was established from tissue biopsies from untreated patients, and additional sublines selected as xenografts for primary resistance to vincristine, melphalan, and ifosfamide. LY186641 was given by oral gavage twice daily for 10 consecutive days or as 5-day courses repeated at 7-day intervals. At the optimal schedule, complete regressions of advanced tumors were obtained in each of the six rhabdomyosarcoma lines. There was no apparent cross-resistance in RMS lines selected for vincristine resistance or against multiple-drug-resistance KB cells in vitro. There was slight cross-resistance in xenografts selected for melphalan resistance, but not in an ifosfamide-resistant line. These results indicate that LY186641 may have significant clinical activity in the treatment of childhood rhabdomyosarcoma.
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PMID:Evaluation of N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)-urea against xenografts of pediatric rhabdomyosarcoma. 259 3

The effect of extracellular pH (pH(e)) on the accumulation and cytotoxicity of the diarylsulfonylurea antitumor agent N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea (MPCU) has been examined. In a human colon adenocarcinoma cell line, GC3/C1, the initial rate of uptake of [3H]MPCU (2.4 microM) was increased by 4.5-fold as pH(e) was reduced from 7.4 to 6.5. Steady state levels of MPCU were inversely proportional to pH(e) and were 5-fold greater at pH 6.0 compared to 7.4. Similar results were obtained using Rh30 cells derived from an alveolar rhabdomyosarcoma. MPCU rapidly re-equilibrated after achieving steady state when pH(e) was altered, indicating that MPCU was not tightly bound within cells. In both cell lines, the uncoupling agent, carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), significantly reduced (GC3/C1) or completely inhibited (Rh30) accumulation of MPCU at each pH(e) examined. Sodium azide had the same effect on the accumulation of MPCU as FCCP. The effects of FCCP and azide appeared to be due to collapse of the pH differential across the mitochondrial inner membrane rather than the gradient across the plasma membrane. As extracellular pH (pH(e)) decreased, intracellular pH(pH(i)) also decreased in GC3/C1 cells, such that the greatest pH differential (pH(i) - pH(e)) was 0.2 units at pH(e) 6.0. Neither FCCP nor azide significantly altered this pH gradient, indicating a minor role, if any, for the plasma membrane pH gradient in accumulation of MPCU in GC3/C1 cells. The effect of pH(e) (7.4 to 6.0) on cytotoxicity of MPCU was determined after exposure of cells for 4 hr to various concentrations of MPCU in the presence of 10% fetal bovine serum. Decreasing the pH(e) from 7.4 to 6.0 increased the potency of MPCU by 4.7- and 4.5-fold in Rh30 and GC3/C1 cells, respectively. In cells exposed to drug/pH(e) combinations that resulted in 50% reduction in colony forming potential, the steady state levels of [3H]MPCU were similar (range 8.8 +/- 0.9 to 10.56 +/- 0.6 nmol/10(6) cells). These results demonstrate that decrease of pH(e) significantly enhanced the uptake of MPCU accumulation into an FCCP/azide-sensitive compartment, and cytotoxicity of this agent. These data further support the hypothesis that sequestration of diarylsulfonylureas into the FCCP/azide-sensitive compartment (probably mitochondria) was associated with its cytotoxicity. The role of pH(e) in determining therapeutic selectivity of diarylsulfonylureas is discussed.
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PMID:Influence of extracellular pH on the accumulation and cytotoxicity of N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea in human cell lines. 1629 3