Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genasense (formerly known as G-3139), an antisense oligonucleotide specific for Bcl-2, is under development by Genta as an iv drip infusion for the potential treatment of various cancers including melanoma, prostate, breast and colon cancer [3083751. It is in phase III trials for malignant melanoma, for which it has been awarded Fast Track status 1359044]. Genasense received Orphan Drug status in August 2000 [3782331. In September 2000, the company announced that pivotal phase III trials in multiple melanoma, chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML) would be underway by 2001 [382783]. By January 2001, trials in AML and CLL had been initiated 1396512]. As of February 2001, Genta was planning the initiation of two additional, registration quality trials. Pending positive results from these trials, launch of Genasense is anticipated in 2002 13984111. A phase III trial in patients with advanced multiple myeloma at 65 centers in the US, Canada and Great Britain began in February 2001. The trial will examine whether the addition of Genasense can improve response rates, response duration and quality of life compared with dexamethasone therapy alone 13989081. Genta Inc has been issued a patent (US-05831066) for Genasense 1283005]. The patent provides protection to Genta for the composition of Genasense and its analogs. Furthermore, Genta Inc has also been issued two new patents that cover a series of compounds containing new backbone constructions that enhance the antisense affinity of the drug to the target pre-RNA, while the other patent covers the methods for preparation of antisense oligonucleotides containing the new backbone structures 12896851. Genta has already licensed the rights for the use of Bd-2 as a target for antisense- and gene therapy-based treatments from The University of Pennsylvania. The licensing agreements with Chugai Pharmaceutical Co for worldwide marketing and profit sharing places Genta in a favorable position. In January 2001, Needham & Co expected Genasense to have a potential market of 47,700 malignant melanoma patients in the US. The analysts also expected potential patient market sizes of 50,000 (CLL), 21,000 (AML), 136,000 (non-small cell lung cancer; NSLCC) and 180,000 (prostate cancer) in the US. In addition, the analysts predicted that Genasense would be approved for melanoma in the second quarter of 2002, with approvals to follow for CLL (third quarter of 2002), AML (third quarter of 2002) and myeloma (fourth quarter of 2002) 1399251].
 ...
PMID:Genasense (Genta Inc). 1156 20

The components of the apoptotic program are targets for anticancer therapy. Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies (mAb). Oblimersen sodium (G3139, Genasense, Genta Inc., Berkeley Heights, NJ) is an antisense oligonucleotide (AS-ON) compound designed to specifically bind to the first 6 codons of the human bcl-2 mRNA sequence, resulting in degradation of bcl-2 mRNA and subsequent decrease in Bcl-2 protein translation. Oblimersen is the first oligonucleotide to demonstrate proof of principle of an antisense effect in human tumors by the documented downregulation of the target Bcl-2 protein. A growing body of preclinical and clinical evidence suggests that oblimersen synergizes with many cytotoxic and biologic/immunotherapeutic agents against a variety of hematologic malignancies and solid tumors. Randomized clinical trials are currently underway to evaluate the efficacy and tolerability of oblimersen in combination with cytotoxic chemotherapy in chronic lymphocytic leukemia, multiple myeloma, malignant melanoma, and non-small cell lung cancer. In addition, nonrandomized trials are under way to evaluate oblimersen in non-Hodgkin's lymphoma, acute myeloid leukemia, and hormone-refractory prostate cancer. Preclinical data also support the clinical evaluation of oblimersen in additional tumor types, including chronic myelogenous leukemia and breast, small cell lung, gastric, colon, bladder, and Merkel cell cancers. Enhancement of the efficacy of anticancer treatments with oblimersen Bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy, and ongoing clinical trials will test this therapeutic approach.
 ...
PMID:Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. 1216 2

The components of the apoptotic pathway are targets for anticancer therapy. Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies. Oblimersen sodium (G3139, Genasense, Genta Inc, Berkeley Heights, NJ) is an antisense oligonucleotide compound designed to specifically bind to the first six codons of the human bcl-2 mRNA sequence, resulting in degradation of bcl-2 mRNA and subsequent decrease in Bcl-2 protein translation. Oblimersen is the first oligonucleotide to demonstrate proof of principle of an antisense effect in human tumors by the documented downregulation of the target Bcl-2 protein. A growing body of preclinical and clinical evidence suggests that oblimersen synergizes with many cytotoxic and biologic/immunotherapeutic agents against a variety of hematologic malignancies and solid tumors. Randomized clinical trials are currently underway to evaluate the efficacy and tolerability of oblimersen in combination with cytotoxic chemotherapy in chronic lymphocytic leukemia (CLL), multiple myeloma (MM), malignant melanoma, and non-small cell lung cancer. In addition, nonrandomized trials are underway to evaluate oblimersen in non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), and hormone-refractory prostate cancer. Preclinical data support the clinical evaluation of oblimersen in additional tumor types, including chronic myelogenous leukemia, and breast, small cell lung, gastric, colon, bladder (CML), and Merkel cell cancers. Enhancement of the efficacy of anticancer treatments with oblimersen Bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy, and ongoing clinical trials will test this therapeutic approach.
 ...
PMID:Oblimersen sodium (G3139 Bcl-2 antisense oligonucleotide) therapy in Waldenstrom's macroglobulinemia: a targeted approach to enhance apoptosis. 1272 Jan 57

The regulation of apoptosis is an important potential target for anticancer therapy. The mitochondrial Bcl-2 protein inhibits apoptosis and is therefore an important mediator of resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy and monoclonal antibody therapy. Oblimersen (Genasense, Aventis Pharmaceuticals / Genta Inc) is a 18mer antisense-oligonucleotide (ASO), which specifically binds to the first 6 codons of the human bcl-2 mRNA, resulting in degradation and destruction of the mRNA by RNAse H. Subsequently there is a significant decrease of bcl-2 translation. A growing number of preclinical and clinical studies suggests that the combination of cytotoxic therapy with Oblimersen results in synergistic anticancer efficacy in many hematologic and solid tumors. Due to its low toxicity profile, oblimersen is an ideal combination partner with conventional chemotherapy. Three randomized phase-III trials (malignant melanoma, chronic lymphocytic leukemia, multiple myeloma) have recently finished recruitment. The results of these studies will be available by the end of 2003. Based on preclinical data, a lot of nonrandomized phase-II studies on several different tumor types like AML, CML, NHL, prostate cancer and breast cancer are underway. The manipulation of proapoptotic and antiapoptotic factors in favor of proapoptotic factors by inhibition of the bcl-2 protein translation in order to enhance the efficacy of anticancer treatments represents a promising new treatment concept in oncology.
 ...
PMID:[Proapoptotic therapy with oblimersen (bcl-2 antisense oligonucleotide)--review of preclinical and clinical results]. 1471 45

Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies. Oblimersen sodium is an antisense oligonucleotide compound designed to specifically bind to human bcl-2 mRNA, resulting in catalytic degradation of bcl-2 mRNA and subsequent decrease in bcl-2 protein translation. Both small cell and non-small cell lung cancer show baseline and inducible expression of bcl-2, which may contribute to resistance to therapy. Preclinical studies have shown that combining bcl-2 antisense with chemotherapy improves antitumor response, increases apoptosis of tumor cells, and increases survival. Preliminary data from a large international randomized trial in melanoma show a trend toward increased survival and significantly improved response rates and response duration when oblimersen is added to dacarbazine. Phase I studies in small cell lung cancer patients demonstrate that oblimersen can be combined with paclitaxel or carboplatin and etoposide. The combination of docetaxel and oblimersen has been shown to be feasible in Phase I studies and is currently undergoing evaluation in comparison with docetaxel alone as first-line salvage therapy in patients refractory or relapsed after one prior chemotherapy regimen. Enhancement of the efficacy of anticancer treatments with oblimersen bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy.
 ...
PMID:Oblimersen sodium (Genasense bcl-2 antisense oligonucleotide): a rational therapeutic to enhance apoptosis in therapy of lung cancer. 1521 67

Apoptosis, or programmed cell death, is a complex process of cell turnover involved in both normal and pathologic processes in the body. Impairments in the apoptotic pathways contribute to tumorigenesis and the development of tumor resistance to chemotherapy. The proto-oncogene bcl-2 appears to serve a critical antiapoptotic function. Its broad expression in tumors coupled with its role in resistance to chemotherapy-induced apoptosis make bcl-2 a rational target for anticancer therapy. The Bcl-2 antisense drug oblimersen sodium (Genasense) enhances apoptosis alone and in combination with cytotoxic chemotherapy in vitro and in numerous xenograft models of solid tumors and hematologic cancers. Results from xenograft models of melanoma were especially encouraging, prompting melanoma to be identified as an initial human trial candidate. In a phase II trial in patients with advanced malignant melanoma resistant to first-line chemotherapy (including dacarbazine [DTIC-Dome]), three objective responses and three minor responses to oblimersen plus dacarbazine were observed among 14 patients. In a large randomized phase III trial, oblimersen plus dacarbazine showed a near doubling of response rate vs dacarbazine alone and a significant prolongation of progression-free survival. For the primary endpoint of overall survival, a significant benefit for the combination was not seen. The ability of oblimersen to modulate apoptosis suggests a new paradigm of anticancer therapy that has clinical potential in a variety of solid tumors and hematologic malignancies. Further, oblimersen is the first antisense molecule studied in clinical trials for its anticancer properties, opening up an entirely new direction for therapy.
 ...
PMID:Apoptosis, Bcl-2 antisense, and cancer therapy. 1565 Nov 71

G3139 (Genasense), an 18mer phosphorothioate antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 messenger RNA (mRNA), downregulates Bcl-2 protein and mRNA expression in many cell lines. However, both the in vitro and in vivo mechanisms of action of G3139 are still uncertain. The isosequential L-deoxyribose enantiomer L-G3139, which does not downregulate Bcl-2 expression, was synthesized to study the role of the Bcl-2 protein in melanoma cells. Both D-G3139 and L-G3139 bind nonspecifically to basic fibroblast growth factor with approximately the same K(c), and cause highly effective inhibition of net formation in 518A2 melanoma cells on Matrigel. The uptakes of D-G3139 and L-G3139 in melanoma cells were also similar. However, unlike D-G3139, L-G3139 does not produce poly ADP-ribose polymerase-1 and procaspase-3 cleavage at 9.5 h after the initiation of the transfection, but can activate the intrinsic pathway of apoptosis at approximately 48 h. Furthermore, treatment of A375 melanoma human xenografts in severe combined immunodeficiency (SCID) mice demonstrates that tumor growth is not inhibited by L-G3139, whereas D-G3139 significantly inhibits the rate of tumor growth. Furthermore, the immunostimulatory properties of L-G3139 appear to be nil, which differs dramatically from those of D-G3139. In conclusion, profound differences exist between D-G3139 and L-G3139 in vivo despite their similarities in vitro.
 ...
PMID:Comparison of d-g3139 and its enantiomer L-g3139 in melanoma cells demonstrates minimal in vitro but dramatic in vivo chiral dependency. 1723 4

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 5-Methyltetrahydrofolate, 9-aminocamptothecin; AdPEDF.11, AE-37, albumin interferon alfa, alicaforsen sodium, alvocidib hydrochloride, AMG-706, arginine butyrate, avanafil, axitinib, azimilide hydrochloride; BAY-579352, belagenpumatucel-L, beta-lapachone, BHT-3009, BIBW-2992, bremelanotide, BX-471; Casopitant mesylate, cediranib, certolizumab pegol, CH-1504, ChimeriVax-West Nile, clofazimine, CpG-7909, curcumin, Cypher; Dapoxetine hydrochloride, darusentan, diflomotecan, D-methionine, dnaJP1, D-serine, DTPw-HB Hib-MenAC, DTPw-HepB-Hib; E-7010, ecogramostim, edodekin alfa, EGFRvlll peptide vaccine, elcometrine, elcometrine/ethinylestradiol, elsilimomab, enrasentan, ertumaxomab, etalocib sodium, exisulind; Fenretinide, fesoterodine, fingolimod hydrochloride, fontolizumab; Gefitinib, gemtuzumab ozogamicin, ghrelin (human), GV-1001; HTU-PA, human papillomavirus vaccine; Indacaterol, indiplon, interleukin-21, intranasal insulin, irinotecan hydrochloride/floxuridine, ISIS-301012, ispinesib mesylate, ixabepilone; K562/GM-CSF; Lapatinib, L-BLP-25, linezolid, liposome encapsulated paclitaxel, LY-2124275; MC-1, MC-1/lisinopril, MDX-066, melanoma vaccine, MMR-V, multivalent (ACYW) meningitis vaccine; Nilotinib, nobori, nociceptin; Oblimersen sodium, orbofiban acetate, ospemifene; Paliperidone, panitumumab, PEG-filgrastim, PEGylated interferon alfacon-1, perflubutane, pertuzumab, phenserine tartrate, phVEGF-A165, pleconaril, prasugrel, prednisolone sodium metasulfobenzoate; R-411, recombinant malaria vaccine, rhGM-CSF, roflumilast, romidepsin, ruboxistaurin mesilate hydrate; Sirolimus-eluting stent, SR-4554, St. John's Wort extract; Talabostat, Taxus, TGN-255, tifacogin, tiotropium bromide, tolevamer sodium, trabectedin, tretinoin LF; Vatalanib succinate; Yellow fever vaccine, YM-155.
 ...
PMID:Gateways to clinical trials. 1723 18

Oblimersen (Genasense is a Bcl-2 antisense compound that selectively targets Bcl-2 RNA for degradation by RNase H and thereby decreases Bcl-2 protein production. Bcl-2 protein plays a major role in preventing apoptosis and has been linked to chemotherapy resistance in melanoma. Preclinical studies with oblimersen in melanoma cell lines and xenograft models of melanoma have demonstrated downregulation of Bcl-2 protein, induction of apoptosis and enhanced tumor response when combined with chemotherapy. Results of a Phase I/II study have shown that reducing Bcl-2 with oblimersen coincident with the administration of dacarbazine may amplify apoptosis and improve therapeutic outcome. A subsequent Phase III trial showed that the addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes relative to dacarbazine alone based on an intent-to-treat analysis of progression-free survival and response rate (overall, complete and durable), as well as overall survival in patients with normal lactate dehydrogenase. This article reviews the biochemistry, pharmacodynamics and pharmacokinetics, safety and efficacy data related to oblimersen in melanoma.
 ...
PMID:Oblimersen in the treatment of metastatic melanoma. 1754 20

The identification of activated oncogenes, such as the bcl-2, in several types of cancer has made it possible to consider such genes as targets for antitumor therapy. Bcl-2 is an anti-apoptotic protein, whose overexpression is associated with chemotherapy resistant cancer, aggressive clinical course and poor survival. The development of novel targeted gene-silencing strategies, such as those based on the use of antisense oligonucleotides, represents a renewed hope in the treatment of cancer. Within this scope, this review covers the main pre-clinical aspects and the most recent clinical data obtained with Oblimersen sodium (Genta Inc.). Oblimersen is a 18-mer phosphorothioate antisense oligonucleotide designed to bind to the first six codons of the human bcl-2 mRNA. Phase I/II trials indicate that infusion of Oblimersen provides biologically relevant plasma levels that lead to downregulation of target Bcl-2 protein. Moreover, the use of Oblimersen in combination with chemotherapy in a variety of cancers has shown promising response rates with good tolerability. Randomized phase III trials are currently underway to evaluate whether the combined use of Oblimersen with standard treatment is superior to standard treatment alone in chronic lymphocytic leukaemia, malignant melanoma and multiple myeloma. Overall, the enhanced efficacy of anticancer treatments of this bcl-2-targeted antisense therapy represents a promising new apoptosis-modulating strategy.
 ...
PMID:Bcl-2-targeted antisense therapy (Oblimersen sodium): towards clinical reality. 1847 75


1 2 Next >>