Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efficacy of combined high-dose etoposide with standard dose cisplatin was evaluated in patients who had refractory lung cancer after standard chemotherapy. Each patient was given etoposide at 500 mg/m2/day on day 1 to 3 continuously (total dose 1,500 mg/m2) and cisplatin at 80 mg/m2 on day 1. Fifteen patients (7 adenocarcinoma, 5 small cell lung cancer, 2 squamous cell lung cancer and 1 sarcoma, which latter was difficult to distinguish from giant cell carcinoma) were entered in this study. The overall response was 41.7% (5 of 12); five partial response, 6 no change, and 1 progressive disease. Three treatment-related deaths were observed; one resulted from sepsis and two from respiratory failure because of tumor progression. All of the patients developed severe myelosuppression; the mean nadir white blood cell count was 400, and the mean nadir platelet count was 24,000 in 28 evaluable courses. The range of maximum concentration of etoposide determined by HPLC was from 17.4 to 39.1 micrograms/ml. These results suggest that high-dose etoposide combined with a standard dose of cisplatin is effective against refractory lung cancer.
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PMID:[Pilot phase II trial of high-dose etoposide combined with cisplatin in the treatment of refractory lung cancer]. 131 97

Small cell lung cancer (SCLC) tumor progression can involve partial or complete conversion to a more treatment-resistant non-small cell (NSCLC) phenotype. In a cell culture model of this phenomenon, we have previously demonstrated that insertion of the viral Harvey ras gene (v-Ha-ras) into SCLC cell lines with amplification and overexpression of the c-myc gene induced many NSCLC phenotypic features. We now report that the v-Ha-ras gene can also induce morphologic, biochemical, and growth characteristics consistent with the NSCLC phenotype in an N-myc amplified SCLC cell line, NCI-H249. We show that v-Ha-ras has novel effects on these cells, abrogating an SCLC-specific growth requirement for gastrin-releasing peptide, and inducing mRNA expression of three NSCLC-associated growth factors and receptors, platelet-derived growth factor B chain, transforming growth factor-alpha (TGF-alpha), and epidermal growth factor receptor (EGF-R). TGF-alpha secretion and EGF-R also appear, consistent with the induction of an autocrine loop previously shown to be growth stimulatory for NSCLC in culture. These data suggest that N-myc and v-Ha-ras represent functional classes of genes that may complement each other in bringing about the phenotypic alterations seen during SCLC tumor progression, and suggest that such alterations might include the appearance of growth factors and receptors of potential importance for the growth of the tumor and its surrounding stroma.
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PMID:v-rasH induces non-small cell phenotype, with associated growth factors and receptors, in a small cell lung cancer cell line. 216 28

Twenty-one patients with limited (12 cases) or extensive (9 cases) small cell lung cancer entered a pilot study with adriamycin (ADM) plus ifosfamide (IFX) as first line treatment for six planned cycles. ADM was administered at the dose of 60 mg/m2 iv push on day 1 and IFX at 3 g/m2/iv in 1-hour infusion on days 1 and 2. To prevent IFX-induced hemorrhagic cystitis, mercaptoethane sulfonate sodium (Mesna) was given after the administration of IFX at the dose of 500 mg/m2 by iv push four times (hour 0, 4, 8, 12) on days 1 and 2. In the absence of disease progression, chemotherapy was repeated every 3 weeks for 6 cycles. All patients were evaluable for analysis of response, toxicity and survival. The overall response rate clinically and radiologically assessed after four treatment cycles was 95.3% (CR 28.6%, PR 66.7%). However, by continuing the same drug treatment up to the sixth cycle, 7 of 14 partial responders showed tumor progression within the intrathoracic region. Therefore, at the end of the planned chemotherapy program the partial remission rate fell to 33.3%, for a total remission rate of 61.9% and a median total survival of 9 months (range 5 to 36+). The regimen was well tolerated with only one case presenting hemorrhagic cystitis. The results achieved with this drug combination appear comparable to those obtained with other conventional regimens. However, the high response rate achieved after four cycles and the low incidence of marrow toxicity suggest the use of this regimen for a short period with increased dose levels.
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PMID:Pilot study with adriamycin and ifosfamide in small cell lung cancer. 254 May 79

Small cell lung cancer (SCLC) manifests a range of phenotypes in culture that may be important in understanding its relationship to non-SCLCs and to tumor progression events in patients. Most SCLC-derived cell lines, termed "classic" SCLC lines, have properties similar to SCLC tumors in patients, including high expression of neuroendocrine markers and low c-myc oncogene expression. A significant number of SCLC lines characterized as "biochemical or morphologic variant" SCLC lines have decreased levels of endocrine differentiation markers associated with increased proliferative indices, amplification of the c-myc oncogene, and growth patterns and biochemical markers more typical of non-SCLCs. To delineate further the relationships between these phenotypes and the molecular events involved, we have inserted the v-Ha-ras gene in SCLC cell lines with (biochemical variant) and without (classic) an amplified c-myc gene. These two SCLC subtypes had markedly different phenotypic responses to similar levels of expression of v-Ha-ras RNA. No biochemical or morphologic changes were observed in classic SCLC cells. In contrast, in biochemical variant SCLC cells, v-Ha-ras expression induced features typical of large cell undifferentiated lung carcinoma, including adherent monolayer growth patterns, increased cloning efficiency, increased levels of non-SCLC cell markers, ultrastructural characteristics and an acquired resistance to polyamine depletion typical of large cell carcinoma, but not SCLC, in vitro. Expression of v-Ha-ras in biochemical variant SCLC cells directly demonstrates that important transitions can occur between phenotypes of human lung cancer cells and that these may play a critical role in tumor progression events in patients. The findings provide a model system to study molecular events involved in tumor progression steps within a series of related tumor types.
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PMID:v-Ha-ras oncogene insertion: a model for tumor progression of human small cell lung cancer. 284 76

A radioimmunoassay for neuron specific enolase (NSE), a marker of neuroendocrine differentiation, has been evaluated in small cell lung cancer (SCLC). In untreated patients 25/38 (68%) with localized SCLC had raised blood levels of NSE (greater than 13 ng ml-1), in extensive disease 34/39 (87%) patients had raised NSE levels. In patients with non-small cell lung cancer (NSCLC) the serum levels were raised in 16/94 (17%). In extensive tumours of non-pulmonary origin NSE levels were increased in 24/116 (20%) patients. Longitudinal studies indicated a good correlation between the response to chemotherapy and fall of NSE levels. Tumour progression was accompanied by a rising NSE in 25/29 patients, with doubling times of 7-90 days. In patients with progression with a normal NSE the recurrence was a NSCLC. Cerebral metastases occurring as the only recurrence during clinical complete remission were not accompanied by a rise of NSE. Serum NSE levels provides a valuable monitor for SCLC during and after chemotherapy.
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PMID:Evaluation of a radioimmunoassay for neuron specific enolase in small cell lung cancer. 299 4

Twenty-one patients with small cell lung cancer (SCLC) were treated with cyclophosphamide (1250 mg/m2), Adriamycin (40 mg/m2), vincristine (2 mg) every three weeks. Thoracic radiotherapy (3000 rad: 10 or 15 fractions) began four weeks after starting chemotherapy. Patients with brain metastases received cranial irradiation. Thirteen of 19 evaluable patients responded to therapy (four complete responses). Sixteen of 19 had significant intrathoracic response (eight complete). Of the three patients without an intrathoracic tumor response, two had simultaneous progression in systemic locations and only one had intrathoracic progression preceding systemic progression. Intrathoracic relapse preceded systemic relapse in two patients, was simultaneous with it in six and followed systemic relapse in four others. Therefore only three patients had intrathoracic tumor progression or relapse preceding systemic progression or recurrence. The more intensive course of radiotherapy was significantly better in preventing intrathoracic tumor progression. Although intrathoracic tumor control is important, primary failure of therapy or relapse appears to be multifocal. Future attention must be directed toward control of multiple potential sites of relapse.
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PMID:Multifocal relapse after concurrent chemotherapy and radiotherapy of small cell lung cancer. 628 46

From July 1987 to July 1988, 35 patients with non small cell lung cancer, stage IV, were included in a phase II trial (GLOT NPC 87/01). The treatment was as follows: cisplatin 50 mg/m2 day 1, vindesin 3 mg/m2 day 1, mitomycin 6 mg/m2 day 2, and bleomycin 15 mg/day, day 1 + 2 by continuous infusion. The evaluation for response was assessed after three courses of chemotherapy. The results were poor: an objective response was observed in three patients: three partial responses and no complete response. Because of tumor progression (18 patients) or toxicity (three patients), 21 patients did not complete the three cycles of chemotherapy. The median survival rate was 100 days. Toxicity was mild: grade III neutropenia occurred in one patient, grade IV thrombocytopenia was also observed in one patient. We conclude that this treatment has only a poor efficacy in stage IV non small cell lung cancer.
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PMID:[Results of a combination of platinum-vindesin-ametycin-bleomycin (CEMB) in the treatment of stage IV non-small-cell lung cancers]. 751 30

In the United States, small cell lung cancer (SCLC) accounts for about 20% of all cases of lung cancer. Without treatment, tumor progression in patients with SCLC is rapid, with a median survival of 2 to 4 months. Modern chemotherapy has yielded multifold increases in median survival, but only minimal improvements have occurred over the last decade. Combination chemotherapy with etoposide/cisplatin prolongs survival, especially in patients with limited disease. In patients at high risk of toxicity from standard combination chemotherapy, single-agent chemotherapy may have a viable role, but whether its efficacy is comparable to combination regimens must be established in clinical trials. Clearly, new, more effective drugs will be required for any major improvements in the treatment of SCLC. Combined-modality therapy employing chemotherapy and chest irradiation appears to produce excellent cytotoxic effects and is relatively well tolerated in patients with limited disease. A recent meta-analysis of 13 randomized trials showed a modest but significant 14% reduction in the relative mortality rate of patients receiving chemotherapy/chest irradiation vs those receiving chemotherapy alone. Surgery as sole treatment can produce cures in highly selected patients with limited disease and can reduce the rate of local recurrence. The use of surgery after definitive treatment remains experimental and should not be considered other than in controlled clinical trials.
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PMID:Small cell lung cancer. State-of-the-art therapy 1994. 778 1

We examined the genomic status of cyclin-dependent kinase-4 and -6 inhibitors, p16INK4,p15INK4B, and p18, in 40 primary lung cancers and 31 metastatic lung cancers. Alterations of the p16INK4 gene were detected in 6 (2 insertions and 4 homozygous deletions) of 22 metastatic non-small cell lung cancers (NSCLCs; 27%), but none were detected in 25 primary NSCLCs, 15 primary small cell lung cancers (SCLCs), or 9 metastatic SCLCs, indicating that mutation in the p16INK4 gene is a late event in NSCLC carcinogenesis. Although three intragenic mutations of the p15INK4B gene were detected in 25 primary NSCLCs (12%) and five homozygous deletions of the p15INK4B gene were detected in 22 NSCLCs (23%), no genetic alterations of the p15INK4B gene were found in primary and metastatic SCLCs. The p18 gene was wild type in these 71 lung cancers, except 1 metastatic NSCLC which showed loss of heterozygosity. We also examined alterations of these three genes and expression of p16INK4 in 21 human lung cancer cell lines. Alterations of the p16INK4 and p15INK4B genes were detected in 71% of the NSCLC cell lines (n = 14) and 50% of the NSCLC cell lines (n = 14), respectively, but there were none in the 7 SCLC cell lines studied. No p18 mutations were detected in these 21 cell lines. These results indicate that both p16INK4 and p15INK4B gene mutations are associated with tumor progression of a subset of NSCLC, but not of SCLC, and that p15INK4B mutations might also be an early event in the molecular pathogenesis of a subset of NSCLC.
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PMID:Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer. 788 51

Transitions between the small cell lung cancer and the non-small cell lung cancer phenotype occur during clinical tumor progression in small cell lung cancer. We have previously developed a culture model which mimics these transitions. In our model, the insertion of the v-Ha-ras oncogene into c-myc overexpressing NCI-H82 small cell lung cancer cells induces features characteristic of non-small cell lung cancer. We now report that treatment of NCI-H82 cells with 1 microM all-trans-retinoic acid resulted in decreased cellular growth, decreased c-myc mRNA levels, and increased L-myc mRNA levels. Retinoic acid treatment prior to v-Ha-ras insertion also inhibited the typical ras-induced phenotypic transition seen in untreated NCI-H82 cells. In contrast, retinoic acid treatment of NCI-H82 ras cells after ras-induced transition to the non-small cell lung cancer phenotype did not affect cellular phenotype, nor c-myc or L-myc gene expression. These data show that all-trans-retinoic acid, a clinically relevant compound, inhibits small cell lung cancer progression in our in vitro model and alters the expression of the c-myc and L-myc oncogenes. These findings suggest mechanisms for the biological effects of retinoic acid in small cell lung cancer.
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PMID:All-trans-retinoic acid alters myc gene expression and inhibits in vitro progression in small cell lung cancer. 812 93


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