The significance of serum active matrix metalloproteinase-9 in patients with non-small cell lung cancer

Matrix metalloproteinase-9 (MMP-9) plays an essential role for metastasis. The purpose of this study is to investigate the significance of active MMP-9 quantified in serum of patients with non-small cell lung cancer. Immunohistochemical staining of the primary tumors was also performed to analyze how much the secretion of MMP-9 from cancer cells influences the concentration of MMP-9 in serum. The preoperative sera of 39 patients with NSCLC, who underwent an operation at our institution from 1996 to 1999, were taken before the operation. Forty-three samples of sera were drawn postoperatively. Of these 43 samples, 16 sera were taken from patients who suffered with recurrence, 27 sera were taken from patients who did not suffer with recurrence. The serum level of active MMP-9 of preoperative state was 24.3 +/- 21.2 ng/ml, which was higher than that of control was 14.6 +/- 18.8 ng/ml, but no significance was recognized statistically between them (P = 0.0666). The immunoreactivity of MMP-9 was not correlated statistically with serum level of total MMP-9 and active MMP-9. The activity ratio of non-recurrent group was also a lower level than that of recurrent group (P = 0.0082). In conclusion, our results suggest that the concentration of serum active MMP-9 has a possibility of being an available marker to detect a recurrent disease. Our findings strongly suggest that measuring the activity ratio of serum MMP-9 appears to be a potentially useful tumor maker.     

Case report: a young woman with advanced esophageal cancer showing pathological complete response to neoadjuvant chemotherapy (CDDP, 5-FU and ADM)

A 32-year-old woman was admitted to our hospital with dysphagia. An upper gastrointestinal series revealed Borrmann type 2 esophageal cancer in the lower thoracic esophagus. Because direct invasion of the thoracic aorta was suspected, FAP therapy (CDDP, 5-FU and ADM) was given as neoadjuvant chemotherapy. After completion of two courses, her dysphagia resolved and the tumor shrank by over 90%, so radical surgery was performed. No lesions were found when the resected specimen was examined macroscopically. The only histological change was hyperplasia of collagen fibers in the submucosa, lamina propria and adventitia of the esophagus. No cancer cells and no metastases to the lymph nodes were observed. Because the tumor had completely disappeared, the histological effect of chemotherapy was classified as grade 3, i.e., pathological complete response (PCR). The response to FAP therapy was excellent and no serious adverse events occurred. Therefore, this is one of the treatments that should be actively applied in patients who have advanced esophageal cancer with suspected lymph node metastasis and invasion of other organs.     

Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation

We investigated the biological effects of the active oxygen produced by P450s. First, we identified which isoforms of P450 efficiently produced active oxygen using electron spin resonance. Eight forms of P450 purified from rat liver were used. Of these, CYP1A2, 2B1, 2C11 and 3A2 produced hydroxyl radicals efficiently. Phenobarbital (PB) which is a typical inducer of CYP2B1 and 3A2 induced production of hydroxyl radicals by rat liver and ketoconazole, an inhibitor of P450, inhibited production of hydroxyl radicals in vitro. PB is a tumor promoter as well as the P450-inducer. We investigated oxidation of the genomic DNA by the hydroxyl radicals produced by PB-inducible P450 in vitro and in vivo. 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation in vivo was assayed by HPLC. PB strongly induced the production of 8-OHdG in the rat liver. While ketoconazole inhibited the production of 8-OHdG in vivo. These results suggest that active oxygen produced by P450 oxidized genomic DNA and induction of P450 increased oxidative stress that may contribute to tumor initiation and promotion.     

Analysis of gastric cancer with cDNA microarray

Recent advances in cDNA microarray techniques have enabled us to study the expression of many genes simultaneously. As gastric cancer remains one of the most common cancers in Japan, we studied gene expression profiles in gastric cancer by cDNA microarray analysis to determine if it would be clinically useful. We demonstrated two points. First, cDNA microarray might be useful as a prognostic indicator. However, there remain several important problems to be solved and these are discussed. Second, laser microdissection plus cDNA microarray might be useful in determining the specific genes that correlate to cancer metastasis or histological subtype. We review the pros and cons for cDNA microarray analysis in the context of gastric cancer.     

Usefulness of weekly administration of paclitaxel for advanced or recurrent gastric cancer

We report herein the efficacy and feasibility of weekly administration of paclitaxel for advanced/recurrent gastric cancer retrospectively. Eleven patients with advanced or recurrent gastric cancer who had received prior chemotherapy were treated with this regimen. Seventy mg of paclitaxel per m2 dissolved in 250 ml 5% glucose was administered by 1-hour intravenous infusion once a week for 3 weeks followed by 1 week rest. To avoid hypersensitivity reactions, the following short premedication was given to all the patients 1 hour before paclitaxel treatment: Dexamethasone 20 mg intravenously (i.v.), diphenhydramine 50 mg i.v., and ranitidine 50 mg i.v. Treatment cycle was 1 to 23 with an average cycle of 5.4. The response rate was 33% (2/6 with measurable lesions), the median time to progression was 104 days, and the median survival time was 160 days. Grade 3 neutropenia occurred in 27.2% of the patients. Weekly paclitaxel may be a promising regimen as a second-line chemotherapy for advanced/recurrent gastric cancer. However, special attention needs to be paid to the neutropenic adverse effect in gastric cancer patients with poor performance status than 2 (greater).     

Complete response in an elderly patient with advanced gastric cancer treated with TS-1

The patient was an 89-year-old woman whose complaints were anorexia and weight loss. As a result of various examinations, she was diagnosed with advanced gastric cancer, Borrmann 3. TS-1 was administered at 75 mg/day for two weeks followed by one-week discontinvation during hospitalization; This course was then repeated after discharge. Anorexia and weight loss improved after two weeks, and complete response (CR) was obtained after 10 months of treatment. No cancer cells were confirmed by endoscopic biopsy. During this period no severe toxicities occurred. This TS-1 administration schedule appears to be a feasible and effective therapy for elderly patients with advanced gastric cancer.     

Application of metallic stents for both inferior vena cava and biliary obstruction by lymph node involvement in a patient with recurrent hepatocellular carcinoma

The authors experienced a case with obstruction of the inferior vena cava (IVC) and the common bile duct due to a recurrent hepatocellular carcinoma. In order to improve severe edema of the lower extremities and obstructive jaundice, IVC metallic stent as well as biliary stent were applied. A Luminexx stent of 8 cm in length was placed in the bile duct via subcutaneous route after biliary drainage. A spiral zigzag stent of 8 cm in length was also inserted into the IVC through the femoral vein following balloon dilatation of the obstructed portion. Subsequently, jaundice and edema were dramatically improved in a short period of time, which resulted in patient discharge from the hospital. Although the patient died of the cancer in 2 months, the quality of life was well maintained until death.     

Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissection

To characterize molecular mechanism involved in pancreatic carcinogenesis, we analysed gene-expression profiles of 18 pancreatic tumors using a cDNA microarray representing 23,040 genes. As pancreatic ductal adenocarcinomas usually contain a low proportion of cancer cells in the tumor mass, we prepared 95% pure populations of pancreatic cancer cells by means of laser microbeam microdissection, and compared their expression profiles to those of similarly purified, normal pancreatic ductal cells. We identified 260 genes that were commonly upregulated and 346 genes that were downregulated in pancreatic cancer cells. Because of the high degree of purity in the cell populations, a large proportion of genes that we detected as upregulated or downregulated in pancreatic cancers were different from those reported in previous studies. Comparison of clinicopathological parameters with the expression profiles indicated that altered expression of 76 genes was associated with lymph-node metastasis and that of 168 genes with liver metastasis. In addition, expression levels of 30 genes were related to the recurrence of disease. These genome-wide expression profiles should provide useful information for finding candidate genes whose products might serve as specific tumor markers and/or as molecular targets for treatment of patients with pancreatic cancer.     

Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

The putative tumor suppressor CDKN1C is an imprinted gene at 11p15.5, a well-known imprinted region often deleted in tumors. The absence of somatic mutations and the frequent diminished expression in tumors would suggest that CDKN1C expression is regulated epigenetically. It has been, however, controversial whether the diminution is caused by imprinting disruption of the CDKN1C/LIT1 domain or by promoter hypermethylation of CDKN1C itself. To clarify this, we investigated the CpG methylation index of the CDKN1C promoter and the differentially methylated region of the LIT1 CpG island (differentially methylated region (DMR)-LIT1), an imprinting control region of the domain, and CDKN1C expression in esophageal cancer cell lines. CDKN1C expression was diminished in 10 of 17 lines and statistically correlated with the loss of methylation at DMR-LIT1 in all but three. However, there was no statistical correlation between CDKN1C promoter MI and CDKN1C expression. Furthermore, loss of CpG methylation was associated with loss of histone H3 lysine 9 (H3K9) methylation at DMR-LIT1. Histone modifications at CDKN1C promoter were not correlated with CDKN1C expression. The data suggested that the diminished CDKN1C expression is associated with the loss of methylation of CpG and H3K9 at DMR-LIT1, not by its own promoter CpG methylation, and is involved in esophageal cancer, implying that DMR-LIT1 epigenetically regulates CDKN1C expression not through histone modifications at CDKN1C promoter, but through that of DMR-LIT1.