Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients who completed a course of radical radiotherapy for T3 bladder cancer are reviewed. A follow up cystoscopy where tumor response was assessed, was carried out in 272 of the 333 patients of whom 41.2% had complete local regression. Significant factors correlated with complete local tumor regression are described, the most significant being histological grade of the tumor. A higher proportion of patients with complete regression were found among those with Grade 3 cancer (55.7%). Patients who received a central tumor absorbed dose of 55.0 gray or 57.5 gray in 20 fractions over 4 weeks had a significantly higher probability of complete local regression and lasting local control than those who received lower doses. Patients with initial complete local regression had a significantly better probability of survival than those with incomplete regression (p less than 0.0001). There was a significant association between the hemoglobin level at the start of radiotherapy and both local regression and survival. Patients with T3 cancer are more critically selected for treatment by primary radical radiotherapy on the basis of primary tumor size, tumor grade and the patient's plasma urea level. Primary cystectomy may be the more appropriate treatment for a patient with a tumor of more than 7 cm in diameter, a Grade 1 cancer or a plasma urea level of more than 10 mmol/l.
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PMID:Primary radical radiotherapy for T3 transitional cell cancer of the bladder: an analysis of survival and control. 242 78

The effectiveness of a relatively low dose of cyclophosphamide (15 mg/kg CY), melphalan (2.5 mg/kg L-PAM) or the monofunctional form of CY (150 mg/kg MoCY) for the cure of mice bearing a large primary s.c. MOPC-315 tumor and extensive metastases has been shown to be dependent on the cooperation of the drugs' tumoricidal activity with T-cell-dependent antitumor immunity, the latter facilitated by the drug's immunomodulatory activity. Here, we have compared the curative effectiveness of three additional drugs: methyl nitrosourea (MNU), hydroxyurea (OH-urea) and bis-chloroethyl nitrosourea (BCNU). Among these drugs, only a relatively low dose of BCNU (15-20 mg/kg) was effective in curing most mice (85%) bearing a large, late stage tumor. A higher dose of BCNU (40 mg/kg, LD10) was much less effective. After an optimal dose of BCNU, the proliferative capacity of the tumor cells 24 h after therapy was reduced by greater than 97%. However, viable tumorigenic cells were still present in the primary tumor and enhanced T-cell-dependent antitumor immunity was necessary for their eradication. The cured mice were resistant to tumor rechallenge. When a low curative dose of L-PAM was followed by OH-urea, the therapeutic effectiveness was not affected, but when this dose of L-PAM was followed by a high nontoxic dose of MNU (100-150 mg/kg), the therapeutic effectiveness was diminished even though MNU was highly tumoricidal (i.e. greater than 99% inhibition of proliferative activity). Thus, BCNU appears to be similar to CY, L-PAM and MoCY in its mechanism of MOPC-315 tumor eradication. The alkylating activity of CY, L-PAM, MoCY and BCNU appears to be critical for their combined tumoricidal and immunomodulatory effects. Since BCNU is the simplest of these four drugs with respect to metabolic pathway, a further study with BCNU and related constructs may shed some light on the biochemical mechanisms of their mode of action. At least one reason for the ineffectiveness of OH-urea or MNU at either low or nontoxic high doses was poor tumoricidal or immunomodulatory activity, respectively. Thus, it seems important to consider both the tumoricidal and immunomodulatory activities of drugs when developing regimens for effective chemotherapy.
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PMID:Tumoricidal and immunomodulatory activities of drugs and implications for therapy of mice bearing a late stage MOPC-315 plasmacytoma. 323 39

A newly synthesized platinum analogue, cis-1,1-diaminomethylcyclohexaneplatinum(II) sulfate (TNO-6), was compared with cis-diamminedichloroplatinum(II) (cis-DDP) for antitumor activity and nephrotoxicity. Antitumor activity was determined in an IgM immunocytoma model in the LOU/M rat. Tumor cells were inoculated on the left flank, and therapy was started when a tumor diameter of 10 to 30 mm was reached. At the start of the therapy, the primary tumor had already metastasized to the draining lymph node and liver. Both platinum compounds, dissolved in 5% glucose water, induced an almost complete tumor regression within 10 to 14 days (average, 84% tumor load reduction) and prolonged survival, compared to that of nontreated animals. The antitumor activity induced by repeated i.p. administration of cis-DDP and TNO-6 reached its maximum at a dose of 1.0 mg/kg body weight (twice a week for 7 weeks). This treatment regimen resulted in a highest tolerable dose for cis-DDP of 1.0 mg/kg and for TNO-6 of 2.0 mg/kg. However, when rats were treated with a 2.0-mg/kg dose of TNO-6, no increase in antitumor activity was obtained. For both platinum compounds, tumor recurrence occurred in almost all animals within 2 to 7 days after the maximum tumor load reduction. Tumors that recurred were found to be cross-resistant to both platinum compounds tested but were sensitive to treatment with doxorubicin (Adriamycin). With regard to toxicity, repeated administration of TNO-6 (1.0 mg/kg twice a week for 7 weeks) induced less decrease of body weight than did cis-DDP. For TNO-6, even in the highest dose investigated (2.0 mg/kg twice a week for 7 weeks), no nephrotoxicity was observed on histological examination of kidney and blood urea and creatinine values, whereas for cis-DDP nephrotoxicity was still present in the lowest dose investigated (0.5 mg/kg). From the comparison of the antitumor activity and nephrotoxicity of TNO-6 and cis-DDP, administered i.p. in 5% glucose solution, it is concluded that both drugs have comparable antitumor activity and potency. In contrast to the effects of cis-DDP, no nephrotoxicity was observed with TNO-6; thus, TNO-6 might be a good alternative to cis-DDP in avoiding nephrotoxicity during platinum therapy.
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PMID:Antitumor activity, induction of cross-resistance, and nephrotoxicity of a new platinum analogue, cis-1,1-diaminomethylcyclohexaneplatinum(II) sulfate, and of cis-diamminedichloroplatinum(II) in an immunocytoma model in the LOU/M rat. 668 93

We are in an era where the potential exists for deriving comprehensive profiles of DNA alterations characterizing each form of human cancer. Such profiles would provide invaluable insight into mechanisms underlying the evolution of each tumor type and will provide molecular markers, which could radically improve cancer detection. To date, no one type of DNA change has been defined which accomplishes this purpose. Herein, by using a candidate gene approach, we show that one category of DNA alteration, aberrant methylation of gene promoter regions, can enormously contribute to the above goals. We have now analyzed a series of promoter hypermethylation changes in 12 genes (p16(INK4a), p15(INK4b), p14(ARF), p73, APC,(5) BRCA1, hMLH1, GSTP1, MGMT, CDH1, TIMP3, and DAPK), each rigorously characterized for association with abnormal gene silencing in cancer, in DNA from over 600 primary tumor samples representing 15 major tumor types. The genes play known important roles in processes encompassing tumor suppression, cell cycle regulation, apoptosis, DNA repair, and metastastic potential. A unique profile of promoter hypermethylation exists for each human cancer in which some gene changes are shared and others are cancer-type specific. The hypermethylation of the genes occurs independently to the extent that a panel of three to four markers defines an abnormality in 70-90% of each cancer type. Our results provide an unusual view of the pervasiveness of DNA alterations, in this case an epigenetic change, in human cancer and a powerful set of markers to outline the disruption of critical pathways in tumorigenesis and for derivation of sensitive molecular detection strategies for virtually every human tumor type.
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PMID:A gene hypermethylation profile of human cancer. 1130 70

Tumors often display unrestricted cell cycling attributable to a dysfunctional G(1)-S checkpoint. One of the mechanisms leading to such a defect is the inactivation of the cyclin-dependent kinase inhibitor p16(INK4a). Although inactivation of p16(INK4a) is observed in a wide range of tumors, including cutaneous melanoma, genetic alteration of p16(INK4a) is reportedly uncommon in uveal melanoma. Here we show that the p16(INK4a) promoter is hypermethylated in 6 of 12 uveal melanoma cell lines and in 7 of 22 primary uveal melanomas analyzed. Five of seven patients with a methylated primary tumor died of metastatic disease compared with 2 of 15 patients with a nonmethylated primary tumor. We also show that all uveal melanoma cell lines with a hypermethylated p16(INK4a) promoter have lost p16(INK4a) expression but have maintained the expression of p14(ARF). Treatment of uveal melanoma cell lines with 5-aza-2'-deoxycytidine results in demethylation of p16(INK4a) and in reexpression of p16(INK4a) mRNA, which is maintained upon withdrawal of the 5-aza-2'-deoxycytidine. In conclusion, p16(INK4a) promoter methylation appears to be a common event in uveal melanoma and is accompanied by the loss of p16(INK4a) expression.
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PMID:Promoter hypermethylation: a common cause of reduced p16(INK4a) expression in uveal melanoma. 1143 74

Cytoreductive nephrectomy prior to systemic therapy significantly increases survival in patients with metastatic renal cancer. This result is generally ascribed to the benefits of resection of the primary tumor including reduction of tumor burden, removal of a source for growth factors and metastases, and enhanced immune response. On the basis of mathematical models of tumor invasion, we propose that the observed effects of cytoreductive nephrectomy may be caused by resection of the kidney rather than the cancer. The models predict that the graded metabolic acidosis associated with mild renal failure after unilateral nephrectomy may alter the dynamics of the tumor-host interface sufficiently to reduce and even reverse the rate of invasion. A review of patient data from the surgical arm of the Southwest Oncology Group (SWOG) 8949(2) trial demonstrates significantly improved survival in patients who experienced postoperative increase in blood urea nitrogen (BUN) and creatinine compared with those who did not (17-month survival versus 4-month survival; P = 0.0007). This is generally consistent with the predictions of the mathematical models. If confirmed, these results suggest novel and broadly applicable tumor therapies.
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PMID:The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy. 1223 87

Differential gene methylation is observed in a variety of human malignancies. The study of the pattern of methylated genes helps to understand carcinogenesis and to identify potential marker tumor genes for clinical use. The differential methylated genes in undifferentiated nasopharyngeal carcinoma (NPC) of Chinese were studied by methylation-specific polymerase chain reaction (MSP). Methylation status of 11 tumor-associated genes (ARF, caspase-8, CDH1, CDKN2A, CDKN2B, MGMT, MLH1, RASSF1A, THBS1, TP73 and VHL) was studied in 30 primary undifferentiated NPC and paired peripheral blood of 12 patients. The methylation profile of NPC in order of frequency was CDH1 (50%), CDKN2B (50%), THBS1 (50%), RASSF1A (46%), MLH1 (40%), MGMT (28%), CDKN2A (23%), TP73 (20%), caspase-8 (7%), ARF (3%) and VHL (0%). Methylation of at least 1 gene was observed in 93% of primary NPC. Of the 12 patients with at least 1 methylated gene in the primary tumor, all 12 (100%) patients had at least 1 of the methylated gene promoter detectable in their peripheral blood. The results show high frequency of methylation in NPC and the potential of using methylation as peripheral blood tumor marker in screening NPC.
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PMID:Differential gene methylation in undifferentiated nasopharyngeal carcinoma. 1263 81

So far, histopathologic, immunohistochemical and molecular properties of metastatic cutaneous squamous cell carcinomas (CSCCs) are relatively unexplored. In patients with multiple CSCCs, as for instance renal transplant recipients (RTRs), it might prove difficult to identify the primary tumor responsible for metastasis. We report a case of an RTR with multiple CSCCs, one of which metastasized. By using p53 and INK4a-ARF mutation analysis, we identified the responsible primary tumor due to an identical mutation in exon 2 of the INK4a-ARF locus. Archival study yielded 14 cases of metastatic CSCC (present case included). In only 8 of 14 metastases, DNA quality was sufficient to perform PCR reactions. In 7 of 8 metastases, either an INK4a-ARF (6 of 8 cases) and/or p53 (3 of 8 cases) mutation was present. In 6 of 7 cases, the corresponding primary could be identified by an identical mutation in p53 and/or INK4a-ARF. In conclusion, molecular analysis using a combination of p53 and INK4a-ARF mutation analysis can identify the corresponding primary skin tumor in case of CSCC metastases in the majority of cases. This is facilitated by the high frequency of these mutations in metastatic CSCC when compared with frequency spectra reported in the literature in primary CSCCs. The major limitation was formed by insufficient DNA quality in archival tissue.
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PMID:INK4-ARF and p53 mutations in metastatic cutaneous squamous cell carcinoma: case report and archival study on the use of Ink4a-ARF and p53 mutation analysis in identification of the corresponding primary tumor. 1561 67

The purpose of this study was to evaluate the clinical safety of pamidronate when administered at a mean dosage of 1.0 mg/kg IV q28d in 33 tumor-bearing dogs. Biochemical tests of renal function were evaluated before each successive pamidronate treatment. Of 33 dogs treated with pamidronate, 1 dog had clinically relevant increases in serum creatinine and blood urea nitrogen concentrations. The biologic activity of IV pamidronate was assessed prospectively in 10 dogs with appendicular osteosarcoma and was assessed on reductions in urine N-telopeptide excretion (P = .042) and enhanced bone mineral density of the primary tumor measured with dual-energy x-ray absorptiometry (P = .024). Additionally, in these 10 dogs, pamidronate's therapeutic activity was supported by subjective improvement in pain control in 4 of the 10 dogs treated. IV pamidronate appears clinically safe in tumor-bearing dogs and may possess modest biologic activity for managing neoplastic complications associated with pathologic bone resorption.
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PMID:Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement. 1571 51

Glioma, and in particular high-grade astrocytoma termed glioblastoma multiforme (GBM), is the most common primary tumor of the brain. Primarily because of its diffuse nature, there is no effective treatment for GBM, and relatively little is known about the processes by which it develops. Therefore, in order to design novel therapies and treatments for GBM, research has recently intensified to identify the cellular and molecular mechanisms leading to GBM formation. Modeling of astrocytomas by genetic manipulation of mice suggests that deregulation of the pathways that control gliogenesis during normal brain development, such as the differentiation of neural stem cells (NSCs) into astrocytes, might contribute to GBM formation. These pathways include growth factor-induced signal transduction routes and processes that control cell cycle progression, such as the p16-CDK4-RB and the ARF-MDM2-p53 pathways. The expression of several of the components of these signaling cascades has been found altered in GBM, and recent data indicate that combinations of mutations in these pathways may contribute to GBM formation, although the exact mechanisms are still to be uncovered. Use of novel techniques including large-scale genomics and proteomics in combination with relevant mouse models will most likely provide novel insights into the molecular mechanisms underlying glioma formation and will hopefully lead to development of treatment modalities for GBM.
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PMID:Molecular mechanisms in gliomagenesis. 1609 98


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