Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy of the topoisomerase I inhibitor CPT-11 [7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxycamptothec in] has been evaluated against a panel of human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas representing intrinsically chemorefractory malignancies, six lines derived from childhood rhabdomyosarcoma (three embryonal and three alveolar) representing a chemoresponsive histiotype, and sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine, melphalan, and the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan). CPT-11 was given by i.v. administration daily for 5 days each week for 2 weeks (one cycle of therapy) or on the same schedule with cycles repeated every 21 days. The maximum tolerated dose for a single cycle of treatment was 40 mg/kg/dose, and for 3 cycles the maximum tolerated dose was 10 mg/kg/dose. Treatment was started against advanced tumors. Against colon adenocarcinomas CPT-11 administered for one cycle at the maximum tolerated dose caused complete or partial regression (> or = 50% reduction in tumor volume) in 5 of 8 lines. One cycle of CPT-11 therapy caused significant inhibition of tumor growth, without 50% regression, in 2 of 3 other colon adenocarcinomas. Rhabdomyosarcoma xenografts derived from untreated patients were highly responsive to CPT-11, which caused complete regression in 5 of 6 lines even at 20 or 10 mg/kg/dose. CPT-11 retained complete activity against rhabdomyosarcomas selected for resistance to vincristine and caused complete regressions in a line selected for resistance to melphalan that was also completely cross-resistant to topotecan. Of note was the observation that CPT-11 was as active against two xenografts selected for primary resistance to topotecan as it was against the respective parental tumors. Preliminary data indicate that CPT-11, like the topoisomerase I inhibitor topotecan, may have increased therapeutic efficacy when administered at a low dose for protracted periods (3 cycles). A comparison of the efficacy of CPT-11 with topotecan is presented.
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PMID:Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against human tumor xenografts: lack of cross-resistance in vivo in tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin. 850 25

Dysregulated gene expression resulting from abnormal epigenetic alterations including histone acetylation and deacetylation has been demonstrated to play an important role in driving tumor growth and progression. However, the mechanisms by which specific histone deacetylases (HDACs) regulate differentiation in solid tumors remains unclear. Using pediatric rhabdomyosarcoma (RMS) as a paradigm to elucidate the mechanism blocking differentiation in solid tumors, we identified HDAC3 as a major suppressor of myogenic differentiation from a high-efficiency Clustered regularly interspaced short palindromic repeats (CRISPR)-based phenotypic screen of class I and II HDAC genes. Detailed characterization of the HDAC3-knockout phenotype in vitro and in vivo using a tamoxifen-inducible CRISPR targeting strategy demonstrated that HDAC3 deacetylase activity and the formation of a functional complex with nuclear receptor corepressors (NCORs) were critical in restricting differentiation in RMS. The NCOR/HDAC3 complex specifically functions by blocking myoblast determination protein 1 (MYOD1)-mediated activation of myogenic differentiation. Interestingly, there was also a transient up-regulation of growth-promoting genes upon initial HDAC3 targeting, revealing a unique cancer-specific response to the forced transition from a neoplastic state to terminal differentiation. Our study applied modifications of CRISPR/CRISPR-associated endonuclease 9 (Cas9) technology to interrogate the function of essential cancer genes and pathways and has provided insights into cancer cell adaptation in response to altered differentiation status. Because current pan-HDAC inhibitors have shown disappointing results in clinical trials of solid tumors, therapeutic targets specific to HDAC3 function represent a promising option for differentiation therapy in malignant tumors with dysregulated HDAC3 activity.
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PMID:CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma. 2795 29