Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transfer of the human multidrug resistance 1 (MDR1) gene to hematopoietic stem cells offers an approach to overcome the myelosuppression caused by a number of antineoplastic drugs. This study was designed to determine the effect of MDR1 gene transfer on overall P-glycoprotein (P-gp) expression in murine hematopoietic cells. Mice were transplanted with bone marrow cells infected with either of two different MDR1 retroviral vectors. A reverse-transcriptase polymerase chain reaction-based assay was used to quantify expression levels of both endogenous and vector-derived P-gp encoding transcripts in hematopoietic cells of transplanted mice. Expression of both a truncated and full-length MDR1 mRNA species was noted in bone marrow and spleen colony cells. The truncated message resulted from cryptic mRNA splice sites within the MDR1 cDNA and was detected with both vectors. Full-length message levels exceeded those from the endogenous genes in all but one case and roughly approximated that seen in the modestly drug-resistant cell line SW620. We conclude that transfer of MDR1 retroviral vectors resulted in a significant increase in P-gp expression in most cases; however, aberrant splicing of MDR1 transcripts can result in reduced expression of vector-derived P-gp.
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PMID:Expression of retroviral vectors containing the human multidrug resistance 1 cDNA in hematopoietic cells of transplanted mice. 760 85

TAS-106, a RNA polymerase inhibitor, was studied in solid tumors with potential clinical benefit and reasonable tolerability. We conducted a multicenter, international phase II trial of TAS-106 in salvage metastatic or recurrent head and neck squamous cell cancer (HNSCC) and nasopharyngeal cancer (NPC) patients. TAS-106 monotherapy was given at 6.5 mg/m(2) over 24-h continuous infusion every 3 weeks. Translational studies for blood and tissue were included. Twenty-seven enrolled patients experienced the most common drug-related adverse events of neutropenia, fatigue, non-neutropenic fever, injection site reaction, and skin rash/dermatitis. The greater than or equal to grade 3 adverse events included neutropenia (14.8%), febrile neutropenia (7.4%), pneumonia (7.4%), and peripheral neuropathy (3.7%). The overall response rate was 0% in both subgroups; five HNSCC patients had stable disease (median duration 99 days) and four NPC patients had stable disease (median duration of 92.5 days). Median progression-free survival (PFS) for HNSCC patients was 52 days (95% CI 43.0-99.0 days) and 48 days (95% CI 41.0-83.0 days) for NPC. Median overall survival (OS) for HNSCC patients was 175 days (95% CI 92.0-234.0 days) and 280 days (95% CI 107.0-462.0 days) for NPC. The TAS-106 plasma levels were equivalent between Asian and Caucasian patients. There was no significant correlation of tumor UCK2 protein expression levels to TAS-106 efficacy. TAS-106 was reasonably tolerated in patients with platinum-failure HNSCC and NPC. The administration schedule of 24-h continuous infusion prevented neurologic toxicity, but had myelosuppression as its main toxicity. There was no anti-tumor efficacy seen with TAS-106 monotherapy. Future studies will focus on TAS-106 combinations and mechanisms of drug resistance.
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PMID:Phase II study of TAS-106 in patients with platinum-failure recurrent or metastatic head and neck cancer and nasopharyngeal cancer. 2393 Feb 12