In vitro detection of cross-resistant and non-cross-resistant agents with fluorouracil for patients with colorectal cancer.

BACKGROUND: Fluorouracil-based chemotherapy, such as that with 5-fluorouracil (5-FU)/leucovorin, is standard as first-line chemotherapy for advanced colorectal cancer (CRC) in Japan. However, the best agent for second-line chemotherapy after fluorouracil failure is yet to be determined. This study was undertaken to find an appropriate agent for second-line chemotherapy. METHODS: Seventy-five tumor specimens from CRC patients with no prior chemotherapy were obtained operatively and their chemosensitivity to five anticancer agents; i.e., 5-FU, mitomycin C (MMC), cisplatin, docetaxel, and an active metabolite of irinotecan (SN-38), was analyzed in an in vitro chemosensitivity test. In this method, the degree of chemosensitivity was expressed as the percent T/C ratio, where T was the total volume of the tumor colonies in the treated group and C was that of the control group. Pearson's correlation coefficients were used to assess the relationship between two agents. RESULTS: Fifty-eight specimens (colon, 28; rectum, 30) were successfully analyzed. Positive correlations with 5-FU chemosensitivity were verified for the chemosensitivity of MMC, cisplatin, and docetaxel. No correlation with 5-FU chemosensitivity was verified for SN-38 chemosensitivity. Although the functional mechanism of each of the agents differs from that of 5-FU, with the exception of irinotecan, they all had a spectrum closely similar to the 5-FU spectrum. CONCLUSION: Only irinotecan exhibited a spectrum independent of that of 5-FU, thus indicating that it could be an appropriate agent for second-line chemotherapy after fluorouracil failure.

Alterations in the Fhit gene in pancreatic duct adenocarcinomas induced by N-nitrosobis(2-oxopropyl)amine in hamsters.

Alteration of the Fhit gene was investigated in pancreatic duct adenocarcinomas induced by N-nitrosobis(2-oxopropyl)amine (BOP) in Syrian golden hamsters. The animals received 70 mg/kg BOP, followed by repeated exposure to an augmentation pressure regimen consisting of a choline-deficient diet combined with DL-ethionine and then L-methionine and administration of 20 mg/kg BOP. A total of 15 pancreatic duct adenocarcinomas were obtained 10 wk after the beginning of the experiment, and total RNAs were extracted from each for assessment of aberrant transcription of the Fhit gene by reverse transcription-polymerase chain reaction analysis. Aberrant transcripts lacking nucleotides in the regions of nt -75 to 348, nt -15 to 348, or nt -75 to 178 were detected in 11 adenocarcinomas (73.3%). Southern blot analysis of eight tumors did not show any evidence of gross rearrangement or deletion. These results indicated that changes in the Fhit gene occurred frequently and thus may have played a role in the development of pancreatic duct adenocarcinomas induced by BOP in hamsters.

Detection of serum MMPs in tumor-bearing hamsters.

BACKGROUND/PURPOSE: Matrix metalloproteinases (MMPs) have been implicated as playing an important role in cancer invasion and metastasis. MMPs have been identified in various malignancies, including pancreatic duct adenocarcinomas. METHODS: We investigated the circulating level of MMP-2 and MMP-9 in sera from Syrian golden hamsters into which hamster pancreatic duct adenocarcinoma tissues had been transplanted subcutaneously (HPDt hamsters). Northern blot analysis and gelatin zymographic analysis were performed to detect the expression of MMPs and that of tissue inhibitors of metalloproteinases (TIMPs) in HPDt hamsters. RESULTS: Northern analysis revealed overexpression of MMP-2, MMP-9, and TIMP-2 mRNAs in subcutaneous tumors of HPDt hamsters as compared with normal pancreatic tissue. Sera from HPDt hamsters possessed significantly higher levels of serum MMP-2 and MMP-9 than control sera, as determined by gelatin zymographic analysis, and there was a significant correlation between tumor growth and serum MMP levels. CONCLUSIONS: These results indicate that overexpression of MMP mRNAs is involved in the progression of pancreatic duct adenocarcinomas, and that MMP protein expression in hamster sera is associated with the presence of pancreatic duct adenocarcinoma cells. The findings also suggest that serum MMPs could be useful markers for monitoring patients with pancreatic duct adenocarcinomas.

Gender differences in the dihydropyrimidine dehydrogenase expression of colorectal cancers.

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD expression levels are believed to correlate with the 5-FU sensitivity of malignant tumors. In colorectal cancer (CRC), a few previous studies demonstrated that females could benefit more from adjuvant chemotherapy. However, it is still unknown why the effectiveness of postoperative chemotherapy is affected by gender. The objective of this study was to clarify the beneficial differences in 5-FU chemotherapy between genders in patients with the CRC based on DPD expression. Ninety-seven tumor specimens and 92 adjacent normal tissue specimens from 97 patients with the CRC and no prior therapy were obtained. The DPD expression in the tissues was quantified and analyzed based on clinicopathological factors. In the tumor tissue, the DPD expression in females was significantly lower than that in males. In the normal tissues, however, there were no significant differences in DPD expression between genders. In the treatment of CRC, cases who will benefit most because of 5-FU sensitivity; i.e. cases with lower DPD expression, must be given priority. Based on DPD expression, female gender seems to be a predictive factor for a better response to chemotherapy with 5-FU.

Rupture of a bleeding pancreatic pseudocyst into the stomach.

A bleeding pancreatic pseudocyst following pancreatitis is a severe complication that can lead to massive gastrointestinal bleeding. Rupture of such a pseudocyst into the stomach is rare. We report herein a case of rupture of a bleeding pseudocyst into the stomach in a patient who was successfully treated with emergency surgery. A 60-year-old Japanese man with a history of chronic alcoholic pancreatitis with a pancreatic tail pseudocyst was referred to us because of hematemesis. The cavity of the pseudocyst, which was 3 cm in size and whose wall adhered to the stomach, was enhanced by dynamic bolus computed tomography (CT) in the late arterial phase. Splenic angiography revealed a bleeding pseudocyst in the splenic hilum. Embolization of the pseudocyst failed, because of arterial spasm. A distal pancreatectomy, splenectomy, and total gastrectomy were performed. The wall of the pseudocyst consisted of the pancreatic tail, granulation tissue, and the posterior wall of the stomach. The patient's postoperative course was uneventful. In the management of massive bleeding from a pseudocyst, early diagnosis with dynamic bolus CT and angiography is essential. A bleeding pseudocyst should be considered to be a lethal complication, but it can possibly be treated with a combination of angiographic embolization and surgery.

Co-expression of CD44v3 and heparanase is correlated with metastasis of human colon cancer.

Heparanase is an enzyme that degrades extracellular glycoprotein to release heparan sulfate molecules. CD44 variant exon 3 (CD44v3), a receptor for heparan sulfate, generates intracellular signals for cell migration. Production of CD44v3 and expression of heparanase were detected by immunohistochemistry and in situ hybridization, respectively. In 145 cases of colon cancer, heparanase mRNA and CD44v3 protein were detected in 46% and 43%, respectively. Co-expression of heparanase and CD44v3 was found in cases of 12% of Dukes' B, 32% of Dukes' C, and 57% of Dukes' D cases. Survival analysis found a significantly poorer prognosis in patients showing concurrent expression of heparanase and CD44v3 than in patients not showing both (p<0.0001). Concurrent expression of heparanase and CD44v3 might be a mechanism of cancer invasion and metastasis in colon cancer.

Alterations of the Fhit gene in hepatocellular carcinomas induced by N-nitrosodiethylamine in rats.

The present study was conducted to assess whether Fhit gene alterations are a feature of hepatocellular carcinomas (HCCs) induced by N-nitrosodiethylamine (DEN) in male Fischer 344 rats. Animals, 6 wk old, received a single intraperitoneal injection of DEN at a dose of 10 mg/kg body weight, followed by combined treatment with partial hepatectomy and colchicine to induce cell-cycle disturbance and a selection procedure, consisting of 2-acetylaminofluorene and carbon tetrachloride. Fourteen HCCs were obtained 42 wk after the beginning of the experiment; total RNA was extracted for the assessment of aberrant transcription of the Fhit gene by reverse transcriptase-polymerase chain reaction analysis. Aberrant transcripts were detected in nine of the 14 HCCs (64.3%). Sequence analysis showed that these resulted from the absence of nt -9 to 279, nt -9 to 348, nt -98 to 279, nt -26 to 365, or nt -98 to 348. Western blot analysis demonstrated reduced expression of Fhit protein in six of 10 HCCs (60.0%), with a perfect correlation with Fhit gene alterations. These results indicated that changes in the Fhit gene occur frequently and may thus play some role in the development of HCCs induced by DEN in rats.