Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trimetrexate (TMTX), a potent inhibitor of the enzyme dihydrofolate reductase, is biochemically and metabolically similar to methotrexate (MTX). Fundamental differences between TMTX and MTX, however, mandate investigation of TMTX in both MTX-sensitive and MTX-resistant tumors. In a number of phase II clinical trials, the antitumor activity of single-agent TMTX has been variable, in part because of the heterogeneity of doses and schedules used and in part because of diverse patient populations. Single-agent activity has been documented in some commonly occurring tumors, including breast, non-small cell lung, and head and neck cancers. Other tumors with sensitivity to single-agent TMTX include transitional cell carcinomas of the urothelium, prostate cancer, and gastric carcinoma. In a small series of children with renal cell carcinoma, significant clinical activity was suggested. The single-agent activity of TMTX, coupled with the finding that TMTX may act as a biochemical modulator of 5-fluorouracil/leucovorin, suggests that the addition of TMTX to 5-fluorouracil/leucovorin should be investigated further. The possibility that TMTX may both exhibit single-agent activity and modulate the effectiveness of other agents makes combination therapy attractive.
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PMID:Trimetrexate: experience with solid tumors. 942 24

The class I IgG receptor (Fc gamma RI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed immunotherapy in cancer patients with the bispecific antibodies MDX-447 [humanized Fab anti-CD64 x humanized Fab anti-(epidermal growth factor receptor, EGFR)] and MDX-H210 (humanized Fab anti-DC64 x Fab anti-HER2/neu), and with the anti-CD64 monoclonal antibody (mAB) MDX-33 (H22) in the modulation of monocyte CD64 in vivo. In an ongoing phase I/II open-label trial with progressive dose escalation (1-15 mg/m2), patients with treatment refractory EGFR-positive cancers (renal cell carcinoma (RCC), head and neck, bladder, ovarian, prostate cancer and skin cancer) are treated weekly with intravenous MDX-447, with and without granulocyte-colony-stimulating factor (G-CSF). MDX-447 has been found to be immunologically active at all doses, binding to circulating monocytes and neutrophils (when given with G-CSF), causing monocytopenia and stimulating increases in circulating plasma cytokines. MDX-447 is well tolerated, the primary toxicities being fever, chills, blood pressure lability, and pain/ myalgias. Of 36 patients evaluable for response, 9 have experienced stable disease of 3-6 month's duration. The optimal dose and the maximal tolerated dose (MTD) have yet to be defined; dose escalation continues to define better the dose, toxicity, and the potential therapeutic role of this bispecific antibody. Three MDX-H210 phase II trials are currently in progress, all using the intravenous dose of 15 mg/m2 given with granulocyte/macrophage (GM-CSF). These consist of one trial each in the treatment of RCC patients, patients with prostate cancer, and colorectal cancer patients, all of whom have failed standard therapy. At the time of writing, 11 patients have been treated in these phase II trials. Four patients have demonstrated antitumor effects. Patients demonstrating responses include 2 with RCC and 2 with prostate cancer. One RCC patient has had a 54% reduction in size of a hepatic metastatic lesion and the other has had a 49% decrease in the size of a lung metastasis with simultaneous clearing of other non-measurable lung lesions. Regarding the two patients with prostate cancer, one has had a 90% reduction in serum prostate-specific antigen (PSA; 118-11 ng/ml), which has persisted for several months; the other patient with prostate has had a 70% reduction of serum PSA (872 ng/ml to 208 ng/ml) within the first month of treatment. Both patients have also demonstrated symptomatic improvement. In a completed phase I and in ongoing phase I/II clinical trials, patients with treatment-refractory HER2/neu positive cancers (breast, ovarian, colorectal, prostate) have been treated with MDX-H210, which has been given alone and in conjunction with G-CSF, GM-CSF, and interferon gamma (IFN gamma). These trials have been open-label, progressive dose-escalation (0.35-135 mg/m2) studies in which single, and more often, multiple weekly doses have been administered. MDX-H210 has been well tolerated, with untoward effects being primarily mild-to-moderate flu-like symptoms. The MTD has not yet been defined. MDX-H210 is immunologically active, binding to circulating monocytes, causing monocytopenia, as well as stimulating increases in plasma cytokine levels. Furthermore, some patients have evidence of active antitumor immunity following treatment with MDX-210. Antitumor effects have been seen in response to MDX-H210 administration; these include 1 partial, 2 minor, and 1 mixed tumor response; 15 protocol-defined stable disease responses have occurred. (ABSTRACT TRUNCATED)
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PMID:Clinical experience with CD64-directed immunotherapy. An overview. 943 76

Urological malignancies kill over 16,000 people annually in England and Wales. There have been exciting recent developments in our understanding of the molecular pathogenesis of these diseases, although many questions remain unanswered. Three separate genes (WT1, WT2, and WT3) have been implicated in Wilms' tumour development. Patients with von Hippel-Lindau (VHL) syndrome develop renal cell carcinoma and it has been shown that VHL protein inhibits elongin, a cellular transcription factor which controls RNA elongation. Use of molecular markers to identify superficial bladder tumours likely to progress to muscle invasive disease has met with some success. Increased epidermal growth factor receptor (EGFR) and p53 expression, and decreased E-cadherin expression all correlate with tumour progression. Tumours in patients with carcinoma in situ have distinct molecular features. Androgen ablation delays disease progression in men with prostate cancer, but relapse is inevitable. Research has been directed towards elucidating the mechanisms by which prostate cancer 'escapes' hormonal control. Mutations in the androgen receptor have been identified. It is apparent that locally produced growth factors mediate androgen-dependent processes and these too have been implicated in prostate carcinogenesis.
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PMID:The molecular pathology of urological malignancies. 949 53

Artificial neural networks are computer-based statistical models that can be used to imitate biologic neural processes. They have been applied to a variety of problems in medicine, including diagnosis and outcomes predictions. In the area of urologic oncology, these neural networks have been used to assist in the diagnosis of prostate cancer, predicting response to therapy and recurrence in prostate cancer, predicting the presence of renal cell carcinoma in cystic renal lesions, and predicting the presence of occult metastatic disease in nonseminomatous testicular germ cell tumors. This article reviews the basic concepts of artificial neural networks and summarizes their application in urologic oncology. Neural network technology remains in its infancy in urologic oncology, and many more retrospective and prospective studies are needed to determine its clinical utility.
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PMID:Applications of neural networks in urologic oncology. 950 81

Bone is among the most common sites of metastatic disease in cancers of the breast, prostate, and lung. The decision about systemic therapy depends on the histology, presence and extent of extraskeletal disease, and the performance status of the patient. For patients with estrogen-receptor-positive breast cancer or prostate cancer, hormonal treatment represents the treatment of choice. In estrogen-receptor-negative breast cancer, and for patients who have failed hormonal therapy or have liver metastases, chemotherapy should be initiated. All patients with small-cell lung cancer should receive chemotherapy. Bone metastases of differentiated thyroid cancers can be treated with radioisotopes. In non-small-cell lung cancer or renal cell cancer, systemic chemotherapy should be confined to younger patients and patients in good general condition. Radiologic assessment of responses of skeletal metastases to systemic therapy is often difficult. New approaches in measuring bone metabolites in urine might prove helpful.
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PMID:[Systematic hormone- and chemotherapy in the management of skeletal metastases]. 961 83

Three different kinds of alterations in DNA methylation have been observed in urological malignancies. DNA hypermethylation of CpG-rich promoter regions is an important mechanism involved in the inactivation of tumor suppressor and other genes in prostate, renal cell, and bladder carcinoma. Genome-wide hypomethylation is most pronounced in urothelial carcinoma, but also occurs in prostatic cancer. Loss of imprinting may be a primary event in the aetiogenesis of Wilms' tumor and probably contributes to testicular cancer. With respect to alterations in DNA methylation three tumor categories are distinguished: in the development of embryonic tumors, e.g. Wilms' tumor, loss of imprinting is important probably by upsetting the balance between genes promoting or inhibiting proliferation. In tumors with faulty DNA methylation, e.g. renal cell carcinoma, occasional errors in DNA methylation are selected for during tumor development. In tumors with deranged methylation, e. g. in most bladder and prostate carcinomas, the mechanisms establishing methylation patterns are fundamentally disturbed and multiple alterations in DNA methylation are observed. At least one of the enzymes establishing methylation patterns, viz. DNA methyltransferases and demethylases, may be deregulated. Moreover, changes in methyl group metabolism need to be considered. DNA hypermethylation and loss of imprinting act by altering the expression of selected genes, whereas hypomethylation may facilitate transcription and recombination throughout the genome by its effect on the chromatin structure. The combination of all three types of alterations may create genomic instability in tumors with deranged DNA methylation. Regarding a potential clinical use, detection of hypermethylation appears most promising in cancer diagnosis, while parameters reflecting genome-wide hypomethylation may prove useful in the prediction of prognosis. Inhibitors of DNA methylation are being improved and will presumably first be employed against tumors with hypermethylated key tumor suppressor genes.
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PMID:DNA methylation in urological malignancies (review). 962 17

Although the fact that the presence of two or more malignancies in a single patient is not a rare occurrence, metastasis of cancer to cancer is rare. Generally the most frequent donor tumor is a lung cancer, and the most common recipient tumor is a renal cell carcinoma. A rare case of lung cancer with metastasis to prostatic cancer is described. To our knowledge, this report represents the first case of a small cell lung cancer metastasizing to a prostatic cancer.
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PMID:A case of small cell lung cancer metastasizing to prostatic cancer. 970 42

The activities of interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta) were investigated in peripheral whole blood from 30 patients with bladder cancer, 12 patients with renal cell carcinoma, 18 patients with prostatic cancer and 16 healthy subjects. Heparinized blood was cultured in the absence and presence of various concentrations of bacterial lipopolysaccharide (LPS). The culture supernatants were obtained and activities of IL-1 alpha and IL-1 beta were determined by enzyme-linked immunosorbent assay (ELISA). In the absence of LPS stimulation, neither IL-1 alpha nor IL-1 beta was spontaneously produced in blood cultures from patients with bladder cancer, renal cell carcinoma or prostatic cancer compared with control subjects. After stimulation with various concentrations of LPS, blood cultures from patients with bladder cancer, renal cell carcinoma, prostatic cancer, those from control subjects produced IL-1 alpha and IL-1 beta in a dose-dependent manner, and IL-1 beta was predominant in all supernatants. The activities of IL-1 alpha and IL-1 beta showed no significant differences between the patients with bladder cancer, renal cell carcinoma or prostatic cancer and control subjects. This study suggested that the patients with bladder cancer renal cell carcinoma and prostatic cancer did not spontaneously produce IL-1 alpha or IL-1 beta, but that the ability to produce IL-1 alpha and IL-1 beta in response to LPS stimulation was not significantly impaired.
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PMID:Interleukin-1 alpha and interleukin-1 beta production in peripheral whole blood from patients with urological cancer. 971 38

Renal cell carcinoma (RCC) is the most common form of cancer affecting the kidney. There is currently no biochemical marker for this disease. We have shown that serum-immunoreactive prostate-specific antigen (PSA) levels, as measured by the two-site Ciba-Corning ACS:180 immunochemiluminometric assay, are elevated in women with RCC. Although the levels were low (0.13-0.89 microgram/l), serum PSA was clearly measurable prior to surgery in 13 of 17 women (76%) with RCC. Significantly, the PSA levels fell to undetectable after nephrectomy. Seventeen normal women also had undetectable (<0. 1 microgram/l) PSA levels. Two women, who had several serum PSA measurements performed postoperatively, showed a t(1/2) of 2-3 days equivalent to that observed for PSA in men following radical prostatectomy for prostate cancer. The 17 RCCs evaluated in this study consisted of 10 stage A, 4 stage B, and 3 stage C tumors. There was no relationship between tumor size, stage, or serum-immunoreactive PSA level, although the majority of these tumors are low grade. We have shown by reverse transcription-PCR, using PCR primers directed to the NH2 terminal coding region of the KLK3 (PSA) gene and the closely related KLK1 and KLK2 genes, that these genes are not expressed in these tumors. Our findings show, however, that elevated levels of a circulating PSA-like protein are present in women with RCC.
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PMID:A prostate-specific antigen-like protein associated with renal cell carcinoma in women. 981 28

Whether the current generation of cytokine gene-transduced tumor vaccines will show clinical efficacy is under study. Fortunately, the large safety profile so far observed with gene-transduced tumor vaccines can allow outpatient testing in large populations of patients in the adjuvant therapy situation. This will allow large studies statistically powered to see potentially important adjuvant therapy effects in the range that are observed for tamoxifen in breast cancer. For example, the outpatient, adjuvant therapy safety context has been established in the use of GM-CSF gene-transduced autologous prostate cancer vaccines following radical prostatectomy. Similar adjuvant therapy clinical trial efforts are anticipated with allogeneic breast, colon, pancreatic, and ovarian cancer in addition to prostate, renal cell carcinoma, and melanoma. The reverse translation of early clinical data back to basic laboratory research also suggests the field of cytokine gene-transduced tumor vaccine research will remain vibrant. Efforts are currently being directed on optimizing DC activation with polycistronic constructs of cytokine genes, and overexpressing the most relevant tumor-associated peptides. As in the case of antineoplastic drug development, not all lead compounds will become approved drugs in medical oncology. Rigorous yet innovative clinical trial designs will be key to the accelerated identification of cytokine gene-transduced vaccines that improve survival in cancer patients.
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PMID:Ex-vivo gene therapy using cytokine-transduced tumor vaccines: molecular and clinical pharmacology. 986 81


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