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)

Eight patients with epithelial ovarian carcinoma persisting after chemotherapy, selected for having a residual tumor no larger than 1 cm in diameter, were treated intra-peritoneally (i.p.) with recombinant interferon-gamma twice weekly for 3 months. Toxicity consisted of fever and malaise in all patients and a transient rise in hepatic enzyme levels in 3 patients. The cytotoxic function of peripheral blood and peritoneal tumor-associated lymphocytes (TAL) and macrophages (TAM), was studied using cell lines as targets. I.p. IFN-gamma augmented the cytotoxic activity of lymphocytes and mononuclear phagocytes: stimulation was more marked and more frequently observed with TAL and occasionally TAM than with blood effectors, suggesting preferential modulation at the site of tumor growth and IFN administration. Surgical laparotomy revealed that 1 patient had a complete response, 2 a partial response and 2 had stable disease, while 3 patients had progressive disease. In this small series of patients there was no obvious, strict correlation between immunomodulation by IFN-gamma and clinical response. These results indicate that, in contrast to its lack of activity in advanced ovarian carcinoma, IFN-gamma has definite immunomodulatory and antitumor activity in the presence of limited tumor burden.
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PMID:Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy. 156 43

Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms. Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.
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PMID:Phase I and pharmacokinetic study of brequinar sodium (NSC 368390). 236 34

Imiquimod [1-(2-methylpropyl)-1H-imidazo[4,5c]quinolin-4-amine] is a compound of low molecular weight that, when administered p.o., induces interferon-alpha in several animal species and inhibits tumor growth in mice. To determine maximum tolerated dose, toxicity, and biological response in humans, a phase I clinical trial was conducted with 14 eligible cancer patients who received 100-500 mg imiquimod p.o. either once or twice weekly. Imiquimod induced interferon-alpha in serum in 10 of 19 doses of 200-300 mg. Interferon serum levels peaked 8-24 h after treatment and reached a maximum of 23,000 IU/ml in one patient. Significant mean increases (P < 0.01) in serum beta 2-microglobulin (1.5-fold), serum neopterin (3.5-fold), and 2-5A synthetase activity in peripheral blood mononuclear cells (7.9-fold) indicated that 200-300 mg imiquimod had biological and immunological activity in all evaluable patients. Increases in serum interferon, beta 2-microglobulin, and neopterin correlated significantly with dose (P < 0.001). No patient developed measurable antibody to interferon-alpha. Dose-limiting side effects included fatigue, malaise, fever, headache, and lymphocytopenia; no hepatic or renal toxicity or other hematological changes exceeded the normal range. Patients tolerated weekly doses of up to 500 mg, with the longest treatment lasting 4 weeks at 200 mg weekly. Twice-weekly doses up to to 300 mg were tolerated, with the longest twice-weekly treatments being 200 mg for 9 weeks and 100 mg for 25 weeks. No clinical responses were observed. Imiquimod, as an oral inducer of interferon, may have therapeutic usefulness in human cancers, viral infections, and other diseases. However, before initiation of phase II trials, additional work will be required to establish a tolerated dose and schedule for continued administration.
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PMID:Phase I trial of an oral immunomodulator and interferon inducer in cancer patients. 822 54

Androgen ablation therapy is the treatment of choice for the palliation of patients with advanced prostate cancer. In addition to palliation, maximal androgen ablation (MAA), with a combination of medical or surgical castration and an antiandrogen, has been shown to increase the survival of patients with metastatic prostate cancer in at least three large well-conducted trials. A subgroup analysis of these trials has suggested that patients, particularly those with low volumes of metastatic disease, fared much better when treated with MAA than with castration alone. This observation has prompted many clinicians to begin androgen ablation earlier in men with advanced but not necessarily metastatic prostate cancer, thus exposing them to prolonged periods of androgen ablation and its side effects. These include impotence, loss of libido, loss of muscle mass, malaise, and psychological disturbances. In order to offer the putative advantages of early hormone therapy but to mitigate its side effects a number of innovative methods of androgen ablation are under investigation. These include 'sequential androgen blockade' and 'intermittent androgen suppression'. Sequential androgen blockade uses a 5 alpha-reductase inhibitor to reduce the conversion of testosterone to dihydrotestosterone in conjunction with an antiandrogen or androgen-receptor blocker to prevent residual androgen from reaching the androgen receptor. Circulating testosterone levels are not reduced thus minimizing side effects. Intermittent androgen suppression uses combined therapy to rapidly reduce serum testosterone and induce tumor regression. From time to time treatment is stopped and androgen concentrations rise. This method reduces the total time of exposure to castrate levels of androgen and, although prostate-specific antigen levels rise during the second phase of therapy suggesting tumor growth, proponents of this cycling method suggest that this should prolong the time to androgen independence of the tumor. Early results with both methods suggest that the time to progression is long and side effects are minimized as compared to MAA. Large scale trials will be needed to determine the exact risks and benefits of these novel methods of androgen ablation.
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PMID:Innovative approaches to the hormonal treatment of advanced prostate cancer. 926 90

Malignant melanoma is increasing in incidence in this country. Metastatic disease generally responds poorly to most chemotherapy drugs. Immunologic and biologic agents have shown some activity in this disease. Interleukin 4 (IL-4) is a cytokine produced by activated T-lymphocytes with pluripotent activities including growth inhibition of various tumor cell lines in vitro and immune- mediated tumor growth inhibition in in vivo animal tumor models. In this phase II trial, patients with advanced malignant melanoma with no prior systemic therapy for metastatic disease and Southwest Oncology Group performance status 0-1 were treated with recombinant human IL-4 at a dose of 5 micrograms/kg/day by daily subcutaneous injection days 1-28 followed by a 7-day rest period, after which the cycle was repeated. Thirty-six patients were registered to this study. Two patients were ineligible by study criteria. Among the 34 eligible patients, there was 1 complete response, 0 partial responses, 2 stable/no responses, 27 increasing disease/progression, 1 early death, and 3 patients whose assessment was inadequate to determine response. The overall estimated response rate was 3% (1 of 34) with a 95% confidence interval 0.1-15%. The duration of the complete response is 421+ days. Thirty-one of the 34 eligible patients have died. The estimated median survival is 6 months (95% confidence interval 4-9 months). The most common toxicities were elevated liver function tests, nausea/vomiting/diarrhea, malaise/fatigue, edema, headache, myalgias/arthralgias, and fever/chills. Despite promising preclinical growth inhibitory and immunomodulatory effects, IL-4 in this dose and schedule showed only low antitumor activity. Alternative methods and routes of administration or combinations of IL-4 with other cytokines might produce greater antitumor effects.
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PMID:Phase II trial of recombinant human interleukin-4 in patients with disseminated malignant melanoma: a Southwest Oncology Group study. 980 39

Locally-advanced gastric cancer features predominance of prognostically unfavorable histological patterns (infiltrative growth--in 87.9%, tumor grades II-IV--69.5%). Tumor invasion into two adjacent organs or more frequently occurs in totally-involved stomach (65.2+/-9.7%), poorly-differentiated (grade Ill) tumors (44.9+/-4.5%) under-differentiated ones (grade IV) (45.9+/-8.2%). Invasion into one adjacent organ is significantly predominant (p<or=0.05) in tumor localized in the upper third of the stomach (66.2+/-5.4%); exophytic tumor growth (Borrmann I) (100%) and well- differentiated (grade I)--(66.7+/-21.3%).
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PMID:[Characteristics of tumor growth in patients with locally-advanced gastric cancer]. 2188 10