Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary resistance to vincristine (VCR) has been selected in rhabdomyosarcoma xenograft HxRh12 by sequential administration of VCR at 1.5 and subsequently 3 mg/kg/passage. The resistant tumor (HxRh12/VCR-3) was approximately 4-fold resistant to VCR and resistance was stable in the absence of selecting pressure (greater than 2 yr). HxRh12/VCR-3 was 2- to 3-fold cross-resistant to L-phenylalanine mustard (L-PAM) but only slightly cross-resistant to ifosfamide. To determine whether selection for primary resistance to L-PAM conferred cross-resistance to VCR we selected an L-PAM-resistant subline of rhabdomyosarcoma xenograft HxRh28 (HxRh28/L-PAM-13). This tumor was 2- to 3-fold resistant to L-PAM and 3-(p-fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl)-aminophenyl]-L- alanyl-L-methionine ethoxyhydrochloride, cross-resistant to cyclophosphamide and ifosfamide, and completely resistant to VCR under in vivo conditions. Pharmacokinetic studies in HxRh12/VCR-3 showed decreased retention of [G-3H]VCR but not alteration in metabolism. Expression of mdr1, a gene that encodes P-glycoprotein, associated with the multiple drug resistance phenotype, was examined. Expression of mdr1 was detected in both HxRh12 and HxRh28 tumors, sensitive to VCR, but there was no increase in expression in tumors selected for primary resistance to VCR or L-PAM. Data suggest that mechanisms other than those associated with "classical" multiple drug resistance confer resistance in these tumors. In clinical evaluation against childhood rhabdomyosarcoma, L-PAM has demonstrated only slight activity in patients relapsing on conventional therapy (including VCR) but demonstrated marked activity in patients with advanced previously untreated disease. It appears likely, therefore, that cross-resistance between VCR and L-PAM as demonstrated in this model may have clinical significance.
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PMID:Reciprocal cross-resistance in human rhabdomyosarcomas selected in vivo for primary resistance to vincristine and L-phenylalanine mustard. 289 Apr 32

We have established preclinical models for the development of drug resistance to vincristine (a major drug used in the treatment of pediatric rhabdomyosarcoma) using cell lines. The RD cell line has a mutant P53 phenotype and does not have detectable P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) despite expressing low levels of mdr-1 mRNA, which encodes P-gp and mrp1 mRNA. Resistant variants of RD were derived by exposure to increasing concentrations of vincristine. This was repeated on six occasions, resulting in three cell lines which could tolerate 64 x the IC(50) concentration. Six independent agents were tested for their ability to prevent the development of resistance in this model. Despite at least 10 attempts, resistance did not develop in the presence of the multidrug resistance (MDR) modulators PSC833, VX710, and XR9576. This strongly suggests that these agents may delay or even prevent the development of resistance to vincristine. This was also confirmed in a second rhabdomyosarcoma cell line, Rh30. In contrast, the agents indomethacin (MRP1 modulator), CGP41251 (protein kinase C inhibitor), and dexrazoxane (putative MDR prevention agent) did not affect the development of resistance in the RD model. Characterization of the resistant cell lines indicated the presence of increased mdr-1 and P-gp expression, which resulted in resistance to the agents doxorubicin, etoposide, and vincristine but not cisplatin. The resistance could be modulated using PSC833 or VX710, confirming that functional P-gp is present. No apparent differences were seen between the resistant cell lines derived in the absence and presence of the various agents. These experiments strongly suggest that the development of MDR may be preventable using modulators of MDR and merit clinical studies to test this hypothesis.
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PMID:In vitro prevention of the emergence of multidrug resistance in a pediatric rhabdomyosarcoma cell line. 1159 14