Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human melanoma, G361, which induces cachexia in nude mice, has been shown to produce a proteolysis-inducing factor (PIF) of Mr 24000, which is immunologically identical to that isolated from a cachexia-inducing murine tumour (MAC16). Biosynthetic labelling of G361 cells using a combination of [35S]sulphate and [6-3H]glucosamine gave a single component of Mr 24000 after affinity chromatography employing a murine monoclonal antibody. The material contained both radiolabels and, after digestion with peptide N-glycosidase F, two fragments were produced of Mr 14000 and 10000 also containing both radiolabels. Digestion with O-glycosidase produced three fragments of Mr 14000, 6000 and 4000, the first two of which contained both radiolabels, while the third only contained 3H. This digestion pattern is the same as that previously observed with PIF from the MAC16 tumour and is commensurate with one N-linked sulphated oligosaccharide chain of Mr 10000, one O-linked sulphated oligosaccharide chain of Mr 6000 and a central polypeptide chain of Mr 4000 with some residual carbohydrate. When PIF from G361 cells was administered to female NMRI mice (20 g) a pronounced depression of body weight (1.36+/-0.36 g; P < 0.0001 from control) was observed over a 24 h period without a decrease in either food or water consumption. Body composition analysis showed a significant decrease in the non-fat carcass mass without a change in carcass fat or body water. This result suggests that depletion of lean body mass in mice bearing G361 melanoma arises from the production of PIF.
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PMID:Role of a proteolysis-inducing factor (PIF) in cachexia induced by a human melanoma (G361). 1046 89

A Phase I study of angiogenesis inhibitor TNP-470 was conducted in patients with advanced cancer. TNP-470 (25-235 mg/m2) was administered i.v. over 4 h once a week to patients who had solid tumors refractory to the best available treatment or with a high risk of recurrence and who had normal renal, hepatic, and hematological function and no evidence of coagulopathy. The aims of the study were to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), and the pharmacokinetics of TNP-470 given on a once-weekly schedule. Thirty-six patients, ages 23-75 (median, 54 years), with an Eastern Cooperative Oncology Group performance status of 0-2 were treated. The number of patients at each dose level (mg/m2) were 6 (25), 3 (50), 3 (75), 3 (100), 3 (133), 12 (177), and 6 (235). The principal toxicities of TNP-470 were dizziness, lightheadedness, vertigo, ataxia, decrease in concentration and short-term memory, confusion, anxiety, and depression, which occurred at doses of 133, 177, and 235 mg/m2. Two patients treated at 235 mg/m2 experienced DLT in the form of grade III cerebellar neurotoxicity after 6 weeks of treatment. Overall, these neurological symptoms were dose-related, had an insidious onset, progressively worsened with treatment, and resolved completely within 2 weeks of stopping the drug. One patient with malignant melanoma had stabilization of the previously growing disease for 27 weeks while on the treatment. Two patients, one with adenocarcinoma of the colon and the other with a soft tissue sarcoma, had no clinically detectable disease but were at high risk for recurrence at the initiation of treatment and received 13 months and > 3 years of treatment, respectively, with no evidence of disease recurrence. The remaining patients had progression of their disease after 1-6 months of treatment. The mean plasma half-life (t(1/2)) of TNP-470 and its principal metabolite, AGM-1883, were extremely short (harmonic mean, t(1/2) of 2 and 6 min, respectively) with practically no drug detectable in the plasma by 60 min after the end of the infusion. MII, an inactive metabolite, had a considerably longer t(1/2) of approximately 2.6 h. Mean peak TNP-470 concentrations were > or = 400 ng/ml at doses > or = 177 mg/m2. On the basis of this study, the maximum tolerated dose of TNP-470 administered on a weekly schedule was 177 mg/m2 given i.v over 4 h. The principal DLT was neurotoxicity, which appeared to be dose-related and was completely reversible. On the basis of the short plasma t(1/2) of TNP-470, exploration of a prolonged i.v. infusion schedule is warranted.
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PMID:A Phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer. 1047 76

Interferon-alpha (IFN-alpha) is of high interest in the adjuvant treatment of malignant melanoma. During long term treatment, psychiatric side effects play an important role and not infrequently lead to reduction or discontinuation of therapy. Most common are sleeping disturbance, agitation, weariness, sleepiness, irritability, social withdrawal and depression, which most often develop during the first three months of the therapy. Also more severe side effects may occur, like delirium, organic depression, psychotic episodes and organic personality change, which in some patients may even lead to suicidal thoughts or suicide attempts, which is illustrated in two case reports. Therapeutic intervention depend to the severity of side effects. Moderate depressive syndromes may successfully be treated by antidepressive drugs like serotonin reuptake inhibitors (SSRI), which may even allow continuation of IFN-alpha therapy. In patients with severe depression or organic personality changes with increased risk of suicide, immideate discontinuation of IFN-alpha therapy is mandatory and treatment in a psychiatric hospital must be considered.
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PMID:[Psychiatric side effects during adjuvant therapy with interferon-alphain patients with malignant melanoma. Clinical evaluation as well as diagnostic and therapeutic possibilities]. 1050 82

The increasing use of interferon (IFN) in treating a variety of disorders including, malignant melanoma and hepatitis C, has resulted in the identification and increasing concern about the psychiatric side effects that can result from treatment. These effects can occur either shortly after beginning IFN therapy or later as a result of continued treatment. Studies have reported the incidence of later side effects, which include symptoms of depression, anxiety, and occasional suicidal ideation, to be from 0% to 70%. Case studies have demonstrated that pharmacologic interventions are beneficial in reducing iatrogenic psychiatric symptoms while allowing patients to maintain IFN therapy. The present article provides an overview of the psychiatric effects of IFN therapy, the proposed mechanisms of these side effects, and case studies that provide mechanistic support. In addition, limitations of the current literature are provided with suggestions for treating physicians and a discussion of possible future research directions.
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PMID:Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions. 1082 53

Tumour patients are subject to different degrees of psychosocial distress depending on the course of disease, personality variables and amount of social support available. Often patients do not spontaneously talk about their distress and attending physicians fail to detect it. Therefore, it is important that the presence of distress is ascertained by specific screening instruments so that appropriate supportive measures can be instituted. The Hornheide Questionnaire (HQ) employed for investigating the need for psychosocial support in the case of patients with skin tumours and with tumours in the head and neck region represents such a specific screening instrument. The present study investigates the validity of the HQ on the basis of two representative samples from two different University Clinics for treatment and follow-ups of melanoma patients. With the help of the HQ, 215 patients at the Dermatology Out-patient Unit of the University of Innsbruck and 223 patients at the University of Freiburg were investigated with regard to their subjective experience of distress. The external constructive validity criteria were established on the basis of the Freiburg Questionnaire of Disease-Coping, the questionnaire of social support and Beck's Depression Inventory. There were significant differences between individuals in the severity of distress in different age groups and in patients in different tumour stages. The internal consistency of the HQ and its subscales proved to be satisfactory demarcation from other psychosocial dimensions and an adequate correlation with similar dimensions (depression, depressive illness coping, social support, compliance). The HQ appears to be an economical and valid screening instrument for detecting the need for psychosocial support in melanoma patients in the out-patient follow-up stage.
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PMID:[The validity of the Hornheide questionnaire for psychosocial support in skin tumor patients: a survey in an Austrian and German outpatient population with melanoma]. 1122 22

Our laboratory has synthesized and evaluated the anticancer activity of a number of sulfonylhydrazine DNA modifying agents. As a class, these compounds possess broad spectrum antitumor activity, demonstrating significant activity against a variety of experimental murine tumors, including the P388 and L1210 leukemias, B16 melanoma, M109 lung carcinoma, and M5076 reticulum cell sarcoma, as well as against the human LX-1 lung carcinoma xenograft. The current report describes the activity of a more recently synthesized member of this class, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine (101M). 101M was active in mice against the i.p. implanted L1210 leukemia over a wide range of doses and produced long-term survivors when administered as a single i.p. bolus of 10, 20, 40, 60, or 80 mg/kg, demonstrating a wider margin of safety than the nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Curative therapy was achieved with doses of 101M that did not produce depression of the bone marrow. 101M was also highly effective against the L1210 leukemia when administered by the oral route. The ability of 101M to penetrate the blood-brain barrier and eradicate leukemia cells in the brain was remarkable (>6 log kill). This agent was also curative against L1210 variants resistant to cyclophosphamide, BCNU, or melphalan. Mice implanted with the murine C26 colon carcinoma were also cured by two injections of 10 or 20 mg/kg of 101M. Administration of 101M by two different well-tolerated regimens caused complete regression of established human glioblastoma U251 xenografts in 100% of treated mice, and significant responses were also obtained with 101M against advanced murine M109 lung carcinomas in mice. The broad spectrum of anticancer activity of the sulfonylhydrazine prodrug 101M coupled with the wide range of therapeutic safety exhibited by this agent, makes 101M particularly attractive for further development and clinical evaluation.
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PMID:1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine (101M): a novel sulfonylhydrazine prodrug with broad-spectrum antineoplastic activity. 1130 84

The anticancer efficacy of the new anticancer tripeptide, L-proline-m-bis (2-chloroethyl) amino-L-phenylalanyl-L-norvaline ethyl ester hydrochloride (MF13), was investigated in mice. MF13 showed a therapeutic effect in liquid tumors and induced complete remission even in late stage malignancies. MF13 also inhibited human colon cancer growth in nude mice by more than 85% (volume, p<0.001). It acted in a dose-dependent manner and induced a complete regression of tumor in 20% of the mice when the initial dose was high (15 mg/kg, i.p.). Human melanoma exhibited a response to MF13 similar to colon cancer. Activity of MF13 in murine hepatoma in vivo was stronger than its precursor m-sarcolysin (p<0.001). Tumor cells in peritoneal cavities of the MF13 treated (s.c.) mice underwent an irreversible apoptosis. Side effects of MF13 were the transient depression of hemopoiesis and loss of body weight, which vanished within 9-10 days. LD50 of MF13 of a single i.p. injection was 27 mg/kg (94 mg/m2), 11 times higher than the therapeutic dose of a single injection.
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PMID:High anticancer efficacy of L-proline-m-bis (2-chloroethyl) amino-L-phenylalanyl-L-norvaline ethyl ester hydrochloride (MF13) in vivo. 1149 47

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

We have previously shown that the risk of major depression in patients with malignant melanoma undergoing interferon-alpha (IFN-alpha) therapy can be reduced by pretreatment with the antidepressant, paroxetine. Using dimensional analyses, the present study assessed the expression and treatment responsiveness of specific clusters of neuropsychiatric symptoms over the first three months of IFN-alpha therapy. Forty patients with malignant melanoma eligible for IFN-alpha treatment were randomly assigned to receive either paroxetine or placebo in a double-blind design. Neuropsychiatric assessments were conducted at regular intervals during the first twelve weeks of IFN-alpha therapy and included the 21-item Hamilton Depression Rating Scale, the 14-item Hamilton Anxiety Rating Scale and the Neurotoxicity Rating Scale. Neurovegetative and somatic symptoms including anorexia, fatigue and pain appeared within two weeks of IFN-alpha therapy in a large proportion of patients. In contrast, symptoms of depressed mood, anxiety and cognitive dysfunction appeared later during IFN-alpha treatment and more specifically in patients who met DSM-IV criteria for major depression. Symptoms of depression, anxiety, cognitive dysfunction and pain were more responsive, whereas symptoms of fatigue and anorexia were less responsive, to paroxetine treatment. These data demonstrate distinct phenomenology and treatment responsiveness of symptom dimensions induced by IFN-alpha, and suggest that different mechanisms mediate the various behavioral manifestations of cytokine-induced "sickness behavior."
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PMID:Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. 2654 64

Elevated magnetic field exposures are associated with increased childhood leukaemia risk. A link with breast and other cancers has been postulated via modified melatonin activity. Other illnesses have been linked to electricity distribution, by association or mechanistic considerations. For selected illnesses, this paper estimates the annual number of excess cases that might occur near high-voltage powerlines in the UK. Within 150m of powerlines, magnetic field exposures above 0.1 microT are postulated to result in 9000 excess cases of depression in adults and 60 cases of suicide. Electric field effects can mediate increased exposure to air pollution. Within 400m of powerlines, this may result annually in 200-400 excess cases of lung cancer, 2000-3000 cases of other illnesses associated with air population and 2-6 cases of childhood leukaemia. Seventeen cases of non-melanoma skin cancer might occur by exposure directly under powerlines.
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PMID:Does our electricity distribution system pose a serious risk to public health? 1216 Jun 79


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