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)

Myeloablation and immunosuppression were considered to be the two major roles of the conditioning regimens for allogeneic stem cell transplantation to facilitate engraftment. It has turned out, however, that immunosuppression is more important and myeloablation is not necessary for engraftment. At the same time, it is considered that the major anti-tumor effect of allogeneic stem cell transplantation depends on the graft-versus-leukemia effect, not on the conditioning regimen itself. In patients with CML who relapsed after allogeneic transplantation, for example, infusion of donor lymphocytes can induce a second complete remission. Non-myeloablative stem cell transplantation (NST) was developed in the late 90s based on these theories. Low-dose, less toxic, so-called "non-myeloablative" preparative regimens have been designed not to eradicate the malignancies, but to provide sufficient immunosuppression to allow donor cells to engraft, while the graft-versus-malignancy effects eradicate the tumor. This strategy permits allogeneic transplantation to be used in patients who are not eligible for conventional, often myeloablative, transplantation because of advanced age or organ dysfunction. Non-myeloablative preparative regimens contain purine analogs, such as fludarabine or cladribine. The NST regimen being used at the National Cancer Center Hospital, Tokyo, Japan, consists of cladribine (0.11 mg/kg x 6 days), busulfan (4 mg/kg x 2 days) and rabbit anti-thymocyte globulin (2.5 mg/kg x 4 days). We enrolled 6 patients in this NST protocol so far: 1 with severe aplastic anemia (sibling-PBSCT), 2 with MDS-RA (1 for sibling-PBSCT and 1 for matched uBMT), 1 with AML-CR2 (matched uBMT), 1 with AML-CR3 (sibling-PBSCT), and 1 with relapsed AML (mismatched related PBSCT). All patients achieved engraftment within 14 days with complete donor chimerism. In addition to leukemias, a graft-versus-malignancy effect was also reported in allogeneic NST of solid tumors, such as renal cell carcinoma and malignant melanoma. The long-term efficacy of NST remains to be determined, and further clinical trials are warranted.
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PMID:[Non-myeloablative stem cell transplant]. 1089 4

The Wilms' tumor (WT1) gene participates in leukemogenesis and is overexpressed in most types of leukemia in humans. WT1 is also detectable in many types of lung, thyroid, breast, testicular, and ovarian cancers and melanoma in humans. Initial studies evaluated whether immune responses to murine WT1 can be elicited in mice. Murine and human WT1 are similar. Thus, mouse models might lead to resolution of many of the critical issues for developing WT1 vaccines. C57/BL6 (B6) mice were injected with synthetic peptides from the natural sequence of WT1 containing motifs for binding to major histocompatibility (MHC) class II molecules. Immunization induced helper T-cell responses specific for the immunizing WT1 peptides and antibody responses specific for WT1 protein. Screening of multiple murine cancer cell lines identified 2 murine cancers, TRAMP-C and BLKSV40, that "naturally" overexpress WT1. Immunization with MHC class I binding peptides induced WT1 peptide-specific cytotoxic T-lymphocyte (CTL) that specifically lysed TRAMP-C and BLKSV40. WT1 specificity of lysis was confirmed by cold target inhibition. No toxicity was noted by histopathologic evaluation in the WT1 peptide-immunized animals. WT1 peptide immunization did not show any effect on TRAMP-C tumor growth in vivo. Immunization of B6 mice to syngeneic TRAMP-C elicited WT1-specific antibody, demonstrating that WT1 can be immunogenic in the context of cancer cells. To evaluate whether WT1 might be similarly immunogenic in humans, serum from patients with leukemia was evaluated for pre-existing antibody responses. Western blot analyses showed WT1-specific antibodies directed against the N-terminus portion of the WT1 protein in the sera of 3 of 18 patients with acute myeloid leukemia (AML). (Blood. 2000;96:1480-1489)
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PMID:Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. 1094 95

This case report documents the first karyotypic, fluorescence in situ hybridization, and genetic analysis of an angiomatoid fibrous histiocytoma that arose and recurred in the arm of a 5.5-year-old girl. Complex rearrangements between chromosomes 2, 12, 16, and 17 were noted, as well as deletion in the long arm of chromosome 11. Flow cytometry revealed a normal cell population. The t(12;16) site was further investigated using reverse transcriptase-polymerase chain reaction. We found that the FUS (also known as TLS) gene from 16p11 combined with the ATF-1 gene from 12q13 to generate a chimeric FUS/ATF-1. The FUS gene is rearranged in the t(12;16)(q13;p11) that characterizes myxoid liposarcoma and in acute myeloid leukemia with t(16;21)(p11;q22), while the ATF-1 gene is rearranged in the t(12;22)(q13;q12) found recurrently in clear cell sarcomas (malignant melanoma of soft parts). Thus, the FUS/ATF-1 gene in angiomatoid fibrous histiocytoma is predicted to code for a protein that is very similar to the chimeric EWS/ATF-1 found in clear cell sarcoma.
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PMID:Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11. 1106 92

Deletion of chromosome Xq23 has been reported in a number of solid tumors, including soft tissue sarcoma, malignant melanoma, astrocytoma, and adenocarcinoma. The deleted Xq often occurs in a setting of very complex karyotypic changes. A similar abnormality has also been described in rare cases of acute myeloid leukemia (AML) but in no other hematologic malignancies. In this study, we report the occurrence of del(X)(q23) in two cases of AML.
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PMID:Deletion of Xq23 is a recurrent karyotypic abnormality in acute myeloid leukemia. 1110 30

This study was conducted to characterise the pharmacokinetics of a liposomal pharmaceutical product of amphotericin B (LAB) in three neutropenic cancer patients complicated by suspected fungal infections. LAB was administered at a constant dose of 50 mg/day over 1--6 h by intravenous infusion, and blood samples were obtained between two infusion intervals without complicating the systemic therapy of the patients. Quantitative analysis of amphotericin B (AB) in plasma was established by a validated reversed-phase high-performance liquid chromatographic (HPLC) assay. Model independent pharmacokinetic parameters were estimated using area and moment analysis. Administration of LAB to the first patient (day 1) diagnosed as malignant melanoma resulted in a mean maximum concentration (C(max)) of 679+/-6 ng/ml and a mean minimum concentration (C(min)) of 139+/-9 ng/ml of AB. Pre-dose, C(max) and C(min) values of AB, after multiple LAB dosing to the other two patients both having acute myeloblastic leukemia were found to be 440+/-6, 1140+/-10, 409+/-11 ng/ml (day 19) and 408+/-3, 1180+/-10, and 283+/-1 ng/ml (day 9), respectively. The area under the plasma concentration-time curve (AUC) and the mean residence time (MRT) calculated between the two infusion intervals were 6180 ngh/ml, 7.79 h (day 1) for the first patient; 13,700 ng.h/ml, 10.5 h (day 19) and 14,000 ng.h/ml, 9.93 h (day 9) for the other two patients, respectively. The pharmacokinetic profiles and non-compartmental parameters calculated were comparable for both patients diagnosed with acute myeloblastic leukemia after multiple dosing at steady state, which also demonstrated a twofold increase in their AUC values compared with the AUC of the first patient. Although C(min) values supported the assumption that there was AB accumulation in plasma and this accumulation could be increased at high doses, LAB was administered safely to these patients and well tolerated at the doses given.
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PMID:Pharmacokinetics of liposomal amphotericin B in neutropenic cancer patients. 1116 3

The aim of this article is to provide an up to date review of second malignant neoplasms (SMN's) following treatment for childhood cancer, referring to their incidence, the role of genetic factors, and how the primary malignancy and treatment received influence the type, site and prognosis of SMN's. The role of genetic factors will be discussed as far as they impact upon a predisposition to later development of SMN's. The primary malignancies that have important associations with SMN's will then be discussed, in particular Hodgkin's disease, retinoblastoma and acute lymphoblastic leukaemia. The important second malignancies will be highlighted, including tumours of the CNS and thyroid, osteosarcoma, secondary acute myeloid leukaemia and melanoma. Emphasis will be put upon identifying which patients are most likely to suffer from these tumours. An important part of the article are case histories. These are provided in combination with illustrations as a useful adjunct to the text, with a particular emphasis on radiological features, diagnosis and screening. Finally, the important but different roles of causal agents, in particular chemotherapy and radiotherapy are highlighted.
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PMID:Second malignancies in children: the usual suspects? 1139 79

The aim of this article is to provide an up to date review of second malignant neoplasms (SMN's) following treatment for childhood cancer, referring to their incidence, the role of genetic factors, and how the primary malignancy and treatment received influence the type, site and prognosis of SMN's. The role of genetic factors will be discussed as far as they impact upon a predisposition to later development of SMN's. The primary malignancies that have important associations with SMN's will then be discussed, in particular Hodgkin's disease, retinoblastoma and acute lymphoblastic leukaemia. The important second malignancies will be highlighted, including tumours of the CNS and thyroid, osteosarcoma, secondary acute myeloid leukaemia and melanoma. Emphasis will be put upon identifying which patients are most likely to suffer from these tumours. An important part of the article are case histories. These are provided in combination with illustrations as a useful adjunct to the text, with a particular emphasis on radiological features, diagnosis and screening. Finally, the important but different roles of causal agents, in particular chemotherapy and radiotherapy are highlighted.
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PMID:Second malignancies in children: the usual suspects? 1122 76

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].
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PMID:Genasense (Genta Inc). 1156 20

Pentostatin (2prime prime or minute-deoxycoformycin, dCF) is a product of the fermentation of Streptomyces antibioticus. It is a tight-binding inhibitor of adenosine deaminase (ADA), an enzyme essential in cellular metabolism of purines. Children with congenital absence of ADA suffer from atrophy of lymphoid tissues and severe combined immune deficiency (SCID) syndrome. It was speculated that pentostatin would be lymphocytotoxic, and this proved to be the case, promoting its investigation in lymphoid neoplasms. It was anticipated that pentostatin would be most active in neoplasms with high intracellular concentrations of ADA---e.g., acute lymphocytic leukemia (ALL), particularly its T cell variety. Although pentostatin proved to be active in ALL, large doses were required and toxic effects outweighted therapeutic benefits. By contrast, pentostatin proved to be exceptionally active in hairy cell leukemia (HCL), a B cell neoplasm with low intracellular concentrations of ADA. Pentostatin has since been shown to possess activity in chronic lymphocytic leukemia, prolymphocytic leukemia, cutaneous T cell lymphomas, adult T cell lymphoma-leukemia, and low-grade non-Hodgkin's lymphomas. It potentiates the activity of vidarabine against viruses and against the cells of acute myeloid leukemia. Pentostatin is inactive in melanoma and renal carcinoma, but has not been adequately evaluated in other solid tumors. The toxic effects of pentostatin include renal failure, central nervous system (CNS) depression, immunosuppression, keratoconjunctivitis, and opportunistic infections. In the absence of pre-existing bone marrow compromise, pentostatin produces only mild myelosuppression. Aside from its use as an antineoplastic agent, pentostatin has potential applications as an immunosuppresive drug, as an antiviral agent, as an antimalarial compound, and in the protection of cells of the CNS from damage induced by ischemia and anoxia.
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PMID:Pentostatin (2prime prime or minute-Deoxycoformycin): Clinical Pharmacology, Role In Cancer Chemotherapy, and Future Prospects. 1184 52

Interleukin-2 (IL-2) is a promising immunotherapeutic agent for the treatment of metastatic melanoma, acute myelogenous leukemia, and metastatic renal cell carcinoma. While high-dose IL-2 regimens have shown clinical benefit in the treatment of melanoma and renal cell carcinoma, serious dose-limiting toxicities have limited their clinical use in a broader group of patients. Low-dose IL-2 therapy has produced disappointing clinical response rates in melanoma. While the response rates to low-dose IL-2 have been better in renal cell carcinoma, the quality of these responses relative to those seen with high-dose IL-2 therapy remains a concern. The addition of IL-2 to chemotherapeutic regimens (biochemotherapy) has been associated with overall response rates of up to 60% in patients with metastatic melanoma, but this has yet to be translated into a confirmed improvement in survival. It remains to be determined whether further modifications of IL-2-based regimens or the addition of newer agents to IL-2 will produce better tumor response and survival.
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PMID:Interleukin-2: clinical applications. 1206 83


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