Effects of sex difference, gonadectomy and estradiol on N-ethyl-N-nitrosourea-induced trigeminal nerve tumors in rats

The occurrence of trigeminal nerve tumors (TNTs) induced byneonatal administration of N-ethyl-N-nitrosourea (ENU) in WF? LE F₁ (F₁ rats was studied with special reference to sex difference,effect of gonadectomy and estradiol (E₂) administration. Experimentalgroups 1–6 were treated with 40 mg ENU/kg of body weightneonatally. They consisted of male, female, castrated male,ovariectomized female, E₂ pellet (0.1 mg, s.c.) supplementedand gonadectomized male and female rats respectively. Rats ofgroups 7–12 served as the respective controls withoutENU. All the rats were killed at 8 months of age. Levels ofserum E₂ and E₂ receptor (ER) of the TNTs were also examined.It was noted that the incidence of TNT was higher in males (79%)than in females (48%, P < 0.05) and did not change by castrationin males (91%) but increased in ovariectomized female rats (74%,P < 0.05). Administration of E₂ followed by gonadectomy inhibitedthe occurrence of TNTs in male rats (59%) but not in femalerats (60%). No TNT was observed in any control groups. Kidneytumors were the second most frequent tumors next to nervoussystem tumors in the present experiment. The incidence of kidneytumors was much higher in females (38%) than in males (4%, P< 0.05) and decreased by ovariectomy, whereas it increasedin male rats by E₂ administration. ER levels of TNTs and trigeminalnerve tissue were < 1 fmol/mg protein. These results suggestthat in rats treated with ENU neonatally, E₂ has an inhibitoryeffect on the induction of TNTs but may not be regulated throughER. E₂ also shows a promoting effect on kidney tumorigenesis.     

Carcinogenicity of Captafol in F344/DuCrj Rats

Captafol was administered at dietary levels of 0 (control), 750 and 1,500 parts per million (ppm) to groups of 50 male and 50 female F344/DuCrj rats for 104 weeks, and then all animals were maintained without captafol for a further 8 weeks, and killed in week 113. Renal cell carcinoma was found in eight of 50 male rats treated with 1,500 ppm and in one of 50 male rats treated with 750 ppm of captafol. The incidences of renal adenomas, including micro-adenomas, and basophilic altered cell tubules were significantly higher in both sexes treated with captafol than in controls, and the increases were apparently dose-dependent except that of adenomas in females. The incidences of neoplastic and preneoplastic lesions of the kidney in captafol-treated animals were higher in males than in females. Captafol also induced hepatocellular carcinomas in four of 50 female rats in the 1,500 ppm group. The incidences of hyperplastic (neoplastic) nodules and foci of cellular alterations in the liver were also significantly increased in both sexes treated with captafol, the increases being dose-dependent. In conclusion, captafol induced renal cell carcinomas in male rats and hepatocellular carcinomas in female rats.     

Delta-sleep-inducing peptide (DSIP) stimulates the release of immunoreactive Met-enkephalin from rat lower brainstem slices in vitro

We studied whether delta-sleep-inducing peptide (DSIP) acted on opioid receptor directly or indirectly. DSIP did not have binding activity to any subtype of opioid receptors. DSIP at doses of 1 pM-1 nM significantly stimulated the release of immunoreactive Met-enkephalin (iME) from superfused slices of the rat lower brainstem. The DSIP-induced release of iME was calcium-dependent. These results show that DSIP acts on opioid receptor indirectly by stimulating the release of iME in producing antinociceptive effects.     

Susceptibility to colon carcinogenesis in C3H<-->C57BL/6 chimeric mice reflects both tissue microenvironment and genotype

Considerable rodent strain differences have been documented with regard to susceptibility to colon carcinogens. To clarify mechanisms, chimeras of susceptible strain C3H and relatively resistant strain C57BL/6N (B6) mice were exposed to a colonotropic carcinogen, 1,2-dimethylhydrazine (DMH) and tumor incidence and multiplicity were assessed. In the chimeras, incidence was as high as the C3H level. Multiplicity of lesions of B6 cells was also increased (P<0.001), but maintenance of the strain difference. When tumor localization was analyzed, tumors of B6 genotype in chimeras demonstrated a greater spread of distribution than in the parental case. The chimeric environment may thus stimulate tumor initiation but cell autonomous suppressive factors may be retained.     

A novel approach to advanced carcinoma of the tongue: cases successfully treated with combination of superselective intra-arterial chemotherapy and external/high-dose-rate interstitial radiotherapy

OBJECTIVE: This study sought to evaluate the efficacy and safety of a novel treatment regimen, intra-arterial cisplatin infusion plus external/high-dose-rate radiotherapy. METHODS: Superselective intra-arterial infusion of cisplatin (100-120 mg) was performed concomitantly with external radiotherapy in four patients with locally advanced carcinoma of the tongue. A high-dose-rate brachytherapy boost was performed after combination therapy in all patients. Brachytherapy was performed after external radiotherapy, and the treatment schedule was twice daily, with a fraction of 600 cGy up to a total of 30-48 Gy. RESULTS: All patients completed the therapy as scheduled. There were no vascular or neurological complications. Grade III acute radiation mucositis developed in all patients but this did not necessitate a treatment break. With a mean follow-up period of 35 months, loco-regional control was obtained for all patients. CONCLUSIONS: The combination of weekly administration of intra-arterial cisplatin plus external/high-dose-rate radiotherapy seems effective for advanced carcinoma of the tongue.     

Gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer

BACKGROUND: The objective of this study was to evaluate the efficacy and toxicity of gefitinib as a first-line therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We analyzed 19 patients with advanced NSCLC retrospectively, who were treated with gefitinib as a first-line therapy. These patients were not considered for systemic chemotherapy secondary to co-morbid conditions, poor performance status (PS) or refusal of chemotherapy. RESULTS: Median age 68 years, male/female 10/9, stage III/IV 7/12, smoker/non-smoker 12/7, adenocarcinoma/non-adeno 13/6, PS 0/1/2/3/4 0/4/7/5/3. Four patients had a partial response and the overall response rate was 21.0%. The median survival time was 6.8 months and 1-year survival was 27%. Overall toxicities were mild. Grade (G) 3 diarrhea was observed in one patient and G1 interstitial pneumonia in one. CONCLUSIONS: These results demonstrate that gefitinib is active as a first-line therapy in patients with advanced NSCLC.     

Combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer

In the present article, we report the results of phase I/II combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer. In the phase I study, we could determine the recommended dose for the phase II study with paclitaxel and S-1 to be 120 mg/m2 and 80 mg/m2, respectively. The side effect was not so severe. The overall response was 53%. In conclusion, biweekly paclitaxel and S-1 administration can be safely combined for the treatment of advanced gastric cancer. This combined therapy represents a novel and active treatment regimen with low toxicity and can be defined as safe and effective. Now we are analyzing the result of the phase II study.     

Different expression patterns of intact forms of squamous cell carcinoma antigens between normal and malignant cervical squamous epithelial tissues: nondenaturing polyacrylamide gel electrophoretic analysis

Squamous cell carcinoma antigen (SCCA), a 45-kDa tumor-associated serpin, mainly consists of two highly homologous molecules, SCCA1 and SCCA2, which possess unique proteinase inhibitory properties. Importantly, our previous study demonstrated that an intact structure of SCCAs, and not a cleaved form yielded by interacting with target proteinase, is essential for their function as a serpin. The aim of this study is therefore, to develop a simple method of analyzing expression patterns of intact forms of SCCAs (functional SCCAs) in cervical squamous epithelial tissues and to investigate whether there are any differences in the expression of intact forms of SCCAs between normal and malignant cervical squamous epithelial tissues. We used nondenaturing polyacrylamide gel electrophoresis (PAGE) with immunoblotting. The newly generated antibody, Pab Y2, recognizes only intact form of SCCAs, while the conventional antibody, Mab 27, reacts with the cleaved form of SCCA1 as well as intact forms of SCCAs. Nondenaturing PAGE using Pab Y2 showed that an intact form of SCCAs in the heat-treated tissue extract at 60 degrees C for 2 h was separated into at least five bands, termed as bands A-E from cathode to anode. By comparison with two-dimensional electrophoresis patterns of SCCAs, it was found that the first three bands, i.e. bands A-C, are derived from the intact form of SCCA1, while the other two bands, i.e. band D and E are from the intact form of SCCA2. Specifically, band E, but not band D, of SCCA2 is apparently increased in squamous cell carcinomas compared with normal squamous epithelium. In conclusion, this novel analytical approach will be useful for investigating the different expression patterns of functional SCCAs between normal and malignant cervical squamous epithelial tissues.     

Anti-inflammatory activity of non-nucleoside adenosine deaminase inhibitor FR234938

Adenosine has anti-inflammatory activity. Adenosine deaminase (EC 3.5.4.4) metabolizes extracellular adenosine, resulting in an exacerbation of inflammation. Consequently, it was hypothesized that adenosine deaminase inhibitors produce anti-inflammatory activity by increasing extracellular adenosine concentration. This group recently developed a non-nucleoside adenosine deaminase inhibitor, FR234938, by using rational structure-based drug design. FR234938 inhibits recombinant human adenosine deaminase enzyme competitively. FR234938 inhibits interleukin (IL)-6-dependent immunoglobulin (Ig) M production by SKW6.4 cells, in the presence of adenosine. Inhibitory effect of FR234938/adenosine combination is blocked by an A2a adenosine receptor antagonist. FR234938 also inhibits anti-type II collagen delayed type hypersensitivity (DTH) in a dose-dependent manner, both in the presence and absence of recombinant human adenosine deaminase. Moreover, FR234938 inhibits tumor necrosis factor (TNF)-alpha and IL-10 production in a lipopolysaccharide (LPS)-induced cytokine production model in mice. These results indicate that FR234938 has potential anti-inflammatory activity. Non-nucleoside adenosine deaminase inhibitor FR234938 has good potential as a new type of anti-rheumatic and anti-inflammatory drug, by modulating host-defense concentrations of adenosine.