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

The influence of ethinylestradiol (EE2) and d-norgestrel (d-Ng) was studied in a melanoma cell line producing a tissue-type plasminogen activator (t-PA) very similar to or identical with the t-PA isolated in extracts from human uterus. The cell cultures were exposed to the two contraceptive steroids by addition of EE2 or d-Ng dissolved in a week alcoholic solution to the culture media, in which the released t-PA was assayed by an immunoradiometric method. A strongly stimulating effect of ethanol (0.76% w/v) on the t-PA production was demonstrated. Whereas, EE2 in the concentration of 1.7 X 10(-7)M and d-Ng in the concentration of 8.6 X 10(-7)M both caused a significantly reduced secretion of t-PA, and this effect was independent of whether the cell cultures were grown to confluency in the presence of the two synthetic steroids or not. It was concluded, that the two contraceptive steroids had an inhibitory effect on the production of t-PA in melanoma cell culture.
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PMID:Ethinylestradiol and d-norgestrel regulation of plasminogen activator in a human melanoma cell line. 654 56

The present studies examined the biochemical characteristics which were carried on from parent cells during fusion of human skin fibroblasts (HSF) with spleen cells of BALB/c mice preimmunized with hormone-responsive and nonresponsive human malignant melanoma cells (HMMC-ShA and HMMC-SR). The melanoma cells used as immunogens were either unmodified or preincubated with vibrio cholera neuraminidase (VCN), with estradiol (E), or with progesterone (P). Responsiveness was monitored by (3H) thymidine and (35S) methionine incorporation. Responsiveness to estradiol, concanavalin A (Con A) and to phytoheamagglutinin (PHA) were carried out, whereas malignancy was suppressed extensively in the cloned hybrids. On the immunizing tumor cells, VCN treatment enhanced (3H) thymidine but reduced (35S)-methionine incorporation and malignancy of the estradiol responsive melanoma cells (HMMC-ShA). VCN treatment enhanced (3H)-thymidine incorporation, but had no effect on (35S)-methionine incorporation and malignancy of the estradiol nonresponsive HMMC-SR cells. Estradiol treatment enhanced plasminogen activator (PA) activity and malignancy, whereas progesterone treatment reduced (inhibited) plasminogen activator activity and suppressed malignancy of the immunizing tumor cells. The PA from estradiol-responsive and from nonresponsive melanoma cells differed in their electrophoretic mobility on polyacrylamide gel electrophoresis.
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PMID:Correlation between plasminogen activator activity of immunizing tumor cells and complement-mediated cytotoxic antibodies secreted by cloned hybrid cells. 719 36

Ecteinascidin-743 (ET-743), a tetrahydroisoquinoline alkaloid isolated from the Caribbean tunicate, Ecteinascidia turbinata, is under development by PharmaMar (the pharmaceutical subsidiary of Zeltia), the National Cancer Institute (NCI) and Ortho Biotech, as a potential treatment for several tumor types including breast cancer, lung cancer, ovarian cancer and melanoma. It appears to function by DNA minor groove alkylation, which induces topoisomerase I-mediated protein-linked DNA strand breakage [322446]. ET-743 is an analog of ET-729 [169825]. As of February 1999, it was in phase II trials [326363], [326268], [375811] and, in August 2001, PharmaMar expected phase II trials for breast, ovarian and non-small cell lung cancer to be completed by August 2002 [423408]. In June 2001, the EMEA awarded ET-743 Orphan Drug status for the treatment of soft tissue sarcoma [412446]. The orphan medicinal product designation is designed to expedite the registration of pharmaceuticals for life-threatening or debilitating conditions with low prevalence (< 5 per 10,000 in the EU), for which no satisfactory treatment exists. The designation offers the sponsor several incentives, such as centralized procedure review of the Marketing Authorization Application and, upon approval, ten-year marketing exclusivity throughout Europe for the therapeutic indication for which it was granted. PharmaMar is also collaborating with the European Organization for Research and Treatment of Cancer (EORTC); PharmaMar has obtained the worldwide rights to ET-743, amongst other ecteinascidins, from the University of Illinois [177268]. In August 2001, Dresdner Kleinwort Wasserstein predicted total sales, for all ET-743's indications, of $1 million in 2002, rising through $1106 million in 2007 to $2725 million in 2011 [423408].
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PMID:ET-743 (PharmaMar/NCI/Ortho Biotech). 1176 68

Trabectedin [Ecteinascidin 743, Yondelis, ET 743, NSC 684766] is a tetrahydroisoquinoline alkaloid derived from the Caribbean marine tunicate, Ecteinascidia turbinata. The drug is being developed by PharmaMar (Zeltia) in partnership with Johnson & Johnson Pharmaceutical Research & Development LLC. It was synthetically isolated and developed by the University of Illinois and licensed to PharmaMar; the company has completed the hemisynthesis of agent. Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G(2) phase, while cells at the G(1 )phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. PharmaMar and Ortho Biotech Products (Johnson & Johnson) entered into an agreement in August 2001 for the joint development and commercialisation of trabectedin. PharmaMar retains commercialisation rights in Europe, including Eastern Europe. Ortho Biotech will market the product in the US, Japan and the rest of the world; Tibotec Therapeutics (a division of Ortho Biotech) will commercialise it in the US. PharmaMar will receive an initial payment from Ortho Biotech plus future milestone and royalty payments linked to development targets and sales; the upfront payment would be approximately 20 million US dollars with royalties contributing 10-20% of total sales of the drug. Although details of the licensing transaction for trabectedin were undisclosed, analysts estimate the figure to be around 100 million US dollars. Previously, PharmaMar signed an agreement granting Bristol-Myers Squibb the option to evaluate and develop as many as 12 of PharmaMar's marine-derived anticancer compounds on an exclusive worldwide basis. However, it appears that Bristol-Myers Squibb had chosen not to exercise the option. Trabectedin is undergoing clinical trials in soft tissue sarcoma (Sarcoma in the Phase table), ovarian, breast, endometrial, prostate and non-small-cell lung cancers. PharmaMar indicated in January 2004 that it intends to launch trabectedin in one of these indications in 2006. PharmaMar raised funds from a round of financing in June 2005 that will be used to fund further clinical trials of its anticancer products, including trabectedin. The US FDA granted trabectedin orphan drug status for ovarian cancer in April 2005. Trabectedin also received orphan drug status from the European Commission for the treatment of ovarian cancer in October 2003. This followed a positive opinion by the Committee for Orphan Medicinal Products (COMP) of the EMEA. Trabectedin has undergone a phase II study for the second- or third-line treatment of ovarian cancer in Europe (England and Belgium), the US and Canada. The trial was initiated in October 2002 and evaluated a weekly schedule of trabectedin (0.58 mg/m(2)) via IV infusion for 3 weeks followed by a week of rest. Final results from this study have been presented. A separate phase II trial evaluating the antitumour activity of trabectedin as a second-line therapy in advanced ovarian cancer was conducted by researchers at the Southern Europe New Drugs Organization (SENDO) in Milan, Italy. PharmaMar and Johnson & Johnson are conducting a pivotal (STS-201) trial to compare a weekly and daily dosing regimen of trabectedin among patients with advanced or metastatic soft tissue sarcoma who are unresponsive to standard chemotherapy of doxorubicin and ifosfamide. The randomised, multicentre, open-label trial has completed enrolment of 270 patients during the second quarter of 2005. Positive data from the STS-201 trial have been announced. An independent data monitoring committee has found that interim data supports a positive trend in time to disease progression favouring patients receiving the daily dosing regimen. Consequently, all patients have been offered the option of switching to the daily regimen. Final results from the STS-201 trial will form the basis of MAA re-submission with European regulatory authorities. PharmaMar has held a pre-submission meeting with the EMEA and has presented a formal letter of intent to file for approval of trabectedin for soft tissue sarcoma. Previously, PharmaMar first filed for EU registration of trabectedin for treatment of advanced soft tissue sarcoma in November 2001, which was accepted for review by the EMEA and Swiss Health Authorities. However, the CPMP confirmed its recommendation not to grant trabectedin marketing authorisation in November 2003 following PharmaMar's appeal against the CPMP's negative opinion first announced in July 2003; the opinion was adopted by a majority vote rather than by consensus. Trabectedin was granted orphan drug status in Europe for recurrent soft tissue sarcoma in 2001. It was also granted orphan drug status by the FDA for the same indication in October 2004. Phase I studies are being conducted to evaluate trabectedin in combination with doxorubicin and liposomal doxorubicin for the treatment of soft tissue sarcoma. PharmaMar is also conducting a phase I study of sequential paclitaxel followed by trabectedin in patients with soft tissue sarcoma. At additional dose levels, patients with other tumour types will be enrolled to assess the antitumour activity of the combination. The US NCI has approved and is partially funding a phase I clinical programme to determine the feasibility of using trabectedin to treat children with soft tissue sarcoma and bone sarcoma who are resistant to conventional therapies. PharmaMar has reported that trabectedin can be safely administered to children at doses up to 1100mg given as a 3-hour infusion, and that this dose will be used in further paediatric studies. Trabectedin has completed phase II studies for small round cell sarcoma and rhabdomyosarcoma, which are aggressive tumours occurring predominantly in children. A phase II study evaluating two dosing schedules of trabectedin has been conducted in patients with leiomyosarcomas or liposarcomas refractory to standard doxorubicin + ifosfamide chemotherapy. The study was conducted in Australia, Canada, Russia and the US.
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PMID:Trabectedin: Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766. 1692 93

A 27-year-old white woman was referred for consultation with regard to the presence of extensive multiple keratotic lesions. She began to develop these lesions at the age of 9 years, with healing of the lesions resulting in scar formation. A biopsy was performed at the age of 16 years, but the patient was unsure of the results. Since then, she had not had any treatment or biopsies, and stated that she had not suffered from any health problems during the intervening period. She was most concerned about the tumors on her heels and soles, which caused difficulty with ambulation. The family history was negative for skin diseases, including melanoma, nonmelanoma skin cancer, psoriasis, and eczema, and positive for Type II diabetes mellitus. A relative reported that the patient's grandfather had similar lesions, but the patient's parents and siblings were healthy. She was married and had one child, a 9-year-old daughter. Her child had no skin lesions. The patient's only medication was Ortho-Tricyclene birth control pills. She had no known drug allergies. Physical examination revealed the presence of multiple lesions on her body (Fig. 1). Her left superior helix contained a well-demarcated, dome-shaped nodule with a rolled, mildly erythematous border with a central hyperkeratotic plug. A similar lesion was present in the scaphoid fossa of the left ear and smaller lesions were scattered on her face. Numerous lesions were present on the arms and legs bilaterally, with the majority of lesions being located on the anterior lower legs. There were also lesions present on the palms and soles. The lesions ranged in size from 5 mm to 3 cm, the largest being a verrucous exophytic nodule on the anterior aspect of her left leg. Overall, there appeared to be two distinct types of lesion. One type appeared round, oval, and symmetric with a central keratotic plug, similar to that on the ear. The other type was larger, more exophytic, and verrucous, including the lesions on the volar surfaces. Also present were numerous, irregularly shaped atrophic scars where previous lesions had healed spontaneously. There were no oral lesions or lesions on her fingernails or toenails, and her teeth and hair were normal. A biopsy was obtained from an early lesion on the right dorsal forearm. Histology revealed an exo-/endophytic growth having a central crater containing keratinous material (Fig. 2). The crater was surrounded by markedly hyperplastic squamous epithelium with large squamous epithelial cells having abundant glassy cytoplasm. Some cells were dyskeratotic. Within the dermis was a dense, chiefly mononuclear inflammatory infiltrate. A buttress of epidermis surrounded the crater. The clinical and pathologic data were consistent with keratoacanthomas. Initial laboratory screenings revealed elevated triglycerides and total cholesterol, 537 mg/dL (normal, < 150 mg/dL) and 225 mg/dL (normal, < 200 mg/dL), respectively, with all other laboratory results within normal limits. In anticipation of starting oral retinoid therapy for her multiple keratoacanthomas, she was referred to her primary care physician for control of hyperlipidemia. After her lipids had been controlled, she was placed on isotretinoin (Accutane) 40 mg/day. There was some interval improvement with regression of some lesions leaving atrophic scars. She was also started on topical application of tazarotene (Tazorac) for all nonresolving lesions. Possible side-effects from the isotretinoin occurred, including dry mouth and eyes. After 8 months of isotretinoin, the patient was switched to acitretin (Soriatane) 25 mg to determine whether it might have a more beneficial effect on the resistant lesions. Many of the larger lesions regressed leaving atrophic scars. The dose of acitretin was subsequently increased to 35 mg because the lesions on her heel and the ball of her foot persisted. Almost all of the lesions resolved, except those on her feet, which are slowly regressing. Currently, the patient is on a regimen of acitretin 25 mg once a day with tazarotene 0.1% gel applied directly to the few residual keratoacanthomas on her feet, which are slowly improving.
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PMID:Multiple keratoacanthomas in a young woman: report of a case emphasizing medical management and a review of the spectrum of multiple keratoacanthomas. 1791 Jul 28


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