Comparative dose-response study on the pulmonary carcinogenicity of 1, 6-dinitropyrene and benzo[a]pyrene in F344 rats

The dose dependencies of the lung carcinogenicity of 1, 6-dinitropyrene(1, 6-DNP) and benzo[a]pyrene (BaP) were examined by directinjections of these compounds into rat lungs. A total of 276male F344 rats were divided into 10 groups and given variousdoses of 1, 6-DNP or BaP, or no drug (control group). Both chemicalswere injected into the lung, as suspensions in beeswax-tricaprylinand the animals were then observed for 104 weeks. The incidencesof lung cancer were 0/39 (0%), 4/30 (13%), 13/31 (42%), 22/26(85%) and 6/9 (67%) in groups treated with 0.003, 0.01, 0.03,0.1 and 0.15 mg of 1, 6-DNP respectively, and 1/29 (3%), 7/30(23%) 22/29 (76%) and 9/13 (69%) in those treated with 0.03,0.1, 0.3 and 1.0 mg of BaP respectively. No lung cancer wasfound in control rats. Thus the incidences of lung cancer inducedby 1, 6-DNP and BaP showed significant dose dependence. At equaldoses, the incidence of lung cancer was much higher with 1,6-DNP than with BaP, and the induction of cancer by 1, 6-DNPwas higher even at one-third the dose of BaP. Histologically,most tumours induced by 1, 6-DNP were undifferentiated neoplasms,whereas most of those induced by BaP were well-differentiatedsquamous cell carcinomas.     

The Colon Mucus Test in Comparison with the Fecal Occult Blood Test in the Detection of Gastrointestinal Disease

Abstract: This study was undertaken to assess the diagnostic significance of the colon mucus test (CMT) by which the cancer-associated carbohydrate antigen, β-D-Gal (1 - 3)-D-GalNAc (T antigen) is measured in rectal mucus, chiefly in patients with various alimentary tract diseases. The incidence of a positive CMT was relatively high in colorectal cancer (69%) and gastric cancer (40%), and was similarly high in some benign colorectal diseases such as colonic diverticulum (42%) and colonic polyps (39%), and in gastric polyps (75%). On the other hand, the incidence of a positive CMT in other benign diseases or in healthy controls was less than 10%. A positive CMT was significantly more common in colorectal disease and in gastric tumors (cancer and polyps) than in the other diseases (p < 0.001). Of 28 colonic polyp patients, 20 (71%) had negative fecal occult blood test results (FOBT), and nine of them (45%) had positive CMT results. These results suggest that the CMT may be a useful screening test for alimentary tract disease, particularly colorectal disease and gastric tumors, although its specificity for colorectal cancer is only moderate. Furthermore, a combination assay using FOBT plus CMT may help to improve the diagnostic rate.     

Therapeutic angiogenesis induced by controlled release of fibroblast growth factor-2 from injectable chitosan/non-anticoagulant heparin hydrogel in a rat hindlimb ischemia model

The addition of non-anticoagulant heparin [periodate-oxidized (IO4) heparin] and fibroblast growth factor (FGF)-2 to a viscous water-soluble chitosan (CH-LA) aqueous solution produces an injectable FGF-2/CH-LA/IO4-heparin hydrogel. The purpose of this study was to examine the ability of the injected FGF-2/CH-LA/IO4-heparin hydrogel to induce vascularization and fibrous tissue formation. FGF-2/CH-LA/IO4-heparin hydrogels (100 microL of hydrogel consisting of 20 mg/mL of CH-LA, 2 mg/mL of IO4-heparin, and 50 microg/mL of FGF-2) were subcutaneously injected into the backs of wound healing-impaired diabetic (db/db) mice. Furthermore, the effect of percutaneous injection of FGF-2/CH-LA/IO4-heparin hydrogel at eight sites (25 microL/site) into ischemic left lower limbs of rats was examined from day 4 to at least day 28 postinjection. The injection of FGF-2/CH-LA/IO4-heparin hydrogels into the backs of db/db mice resulted in significant increases in blood vessel formation, significant vascularization, and fibrous tissue formation near the injection site. Injection of FGF-2/CH-LA/IO4-heparin hydrogel into ischemic left lower limbs of rats also significantly recovered and increased blood flow and blood oxygen in the calf and thigh. These results indicate that the controlled release of biologically active FGF-2 molecules from FGF-2/CH-LA/IO4-heparin induces angiogenesis and possibly collateral circulation in db/db mice and the ischemic limbs of rats.     

Epidermal Growth Factor Induces the Expression of Its Receptor Gene in Human Gastric Carcinoma Cell Line TMK-1

To ascertain the possible autocrine pathway in the growth promotion of gastric carcinomas, a study was made on the effects of exogenous human epidermal growth factor (hEGF) on the expression of mRNA for EGF, transforming growth factor-α (TGF-α), EGF receptor, FOS and MYC genes by TMK-1 cells. Exogenous hEGF increased FOS and MYC mRNA levels 30 min and 1 h after the treatment, respectively. TMK-1 cells accumulated the mRNA for EGF receptor about 7- to 8-fold by 3 h after treatment Expressions of mRNA for EGF and TGF-α genes were detected, but the amounts of the mRNA of these genes in TMK-1 cells were not altered after the treatment.     

Correlation between serum pepsinogen levels and gastric mucosal histological findings before and after Helicobacter pylori eradication therapy

Background: Helicobacter pylori causes chronic gastritis and is also associated with many other gastrointestinal diseases. The incidence of gastric cancer is thought to vary according to the degree and topography of chronic gastritis. Histological findings of specimens obtained at endoscopy are therefore important. In the present study, we investigated the correlation between these histological findings and serum pepsinogen (PG) levels. Methods: Helicobacter pylori eradication therapy was conducted in 100 H. pylori‐positive patients. Endoscopies were performed prior to, and 2 months after, eradication therapy; gastric mucosal biopsies were taken from the antrum and corpus. Helicobacter pylori infection was diagnosed using the rapid urease test, culture and histology. Using the Updated Sydney System, histological findings of inflammation, activity, atrophy and intestinal metaplasia were each graded. Blood was taken on the same two occasions for determination of serum levels of PG I and II. Results: Levels of PG I were highest in association with antrum‐predominant gastritis (APG), followed in order by pangastritis (PAN) and corpus‐predominant gastritis (CPG), with a significant difference between APG and CPG. No correlations were seen between PG II levels and gastritis topography. Examination of the relationship between PG levels and histological findings revealed significant correlations between PG I levels after eradication atrophy and intestinal metaplasia in the gastric corpus. No significant correlations were seen between PG II levels and before or after eradication histological findings. Conclusion: Our results indicate that serum PG levels may be a useful indicator of before‐eradication gastritis topography and after‐eradication gastric atrophy in the gastric corpus.     

7-Nitroindazole, a selective inhibitor of neuronal nitric oxide synthase: effect on sevoflurane MAC and cerebellar cyclic GMP in mice

Purpose Considerable evidence suggests that nitric oxide (NO) plays a role in synaptic transmission in the central and peripheral nervous systems. However, whether inhibition of NO synthesis decreases minimum alveolar concentration (MAC) of inhalational anesthetics is controversial. We examined the effects of 7-nitroindazole (7-NI), a selective inhibitor of neuronal NOS (nNOS), on the MAC of sevoflurane and cerebellar cyclic guanosine monophosphate (cGMP) levels in mice. Methods Sevoflurane MAC and cerebellar cGMP levels were determined in mice after acute intraperitoneal or weeklong gavage feeding of 7-NI. Sevoflurane MAC and cerebellar cGMP levels after chronic treatment were measured on days 1, 4, and 7 and were repeated after an acute intraperitoneal dose of nitro ^g -l-arginine methylester (l-NAME). Results Acute and chronic treatment with 7-NI decreased the sevoflurane MAC by 20%–30%. Reduction of cerebellar cGMP levels was greater after intraperitoneal administration of NOS inhibitors than after gavage feeding of 7-NI. Conclusion Acute or chronic selective inhibition of neuronal NOS decreases the sevoflurane MAC and cerebellar cGMP levels in mice. 7-NI permitted probing of the role of NO in perception of noxious stimuli.     

Preferential blockade of the tubulin transport by colchicine

L-[³⁵S]Methionine was injected into the dorsal root ganglion (L₅) of the adult rat, and migration of the neurofilament polypeptides (the triplet with molecular weights of 200,000, 160,000 and 68,000 daltons), - and β-tubulins and actin in the sciatic nerve and the dorsal root was quantitatively determined and also examined by fluorography. Colchicine (4 μg) injected into the ganglion 10 min before methionine preferentially blocked the tubulin transport, with little if any blockade of the triplet and actin. Colchicine at this dose had no effects on the incorporation ofL-[¹⁴C]leucine into the total protein and also into tubulins. In contrast to colchicine, vinblastine sulphate (4 μg) injected into the ganglion in a similar way blocked the transport of all the triplet, tubulins and actin. Cytochalasin D (1 μg) had no effect on the slow axoplasmic transport.     

Multidrug Resistance in Cultured Human Leukemia and Lymphoma Cell Lines Detected by a Monoclonal Antibody, MRK16

Forty cultured human leukemia and lymphoma cell lines never exposed to anticancer agents in culture, apart from doxorubicin (ADM)-resistant K562/ADM, were examined for reactivity with a monoclonal antibody, MRK16 in F(ab')₂ form [MRK16-F(ab')₂], which recognizes P-glycoprotein (P-gp). The relative resistance index to various drugs was calculated by dividing the 50% growth inhibitory concentration (IC₅₀) of the test cell line by IC₅₀ of K562, which was the negative control in the antibody experiment. MRK16-F(ab')₂ reacted with four cell lines, K562/ADM, KYO-1, HEL and CMK, which had relative resistance index values of 2 or more to vincristine (VCR), vindesine, vinblastine, ADM, daunorubicin, mitoxantrone (MIT), etoposide (VP-16) and actinomycin-D (ACT-D). The level of resistance to VCR and ADM in these cell lines decreased significantly in the presence of 10 μ M verapamil in vitro . Significant expression of mRNA of P-gp gene was also detected in K562/ADM, KYO-1 and HEL. MRK16-F(ab')₂ did not react with 36 other cell lines. Among them, three cell lines, PL-21, P31/FUJ and KOPM-28, had relative resistance index values of 2 or more to anthracyclines, MIT and VP-16, but not to vinca alkaloids or ACT-D. The level of ADM-resistance in these cell lines did not decrease significantly in the presence of 10 μ M verapamil. Five cell lines, ATL-1K, HL-60, KMOE-2, ML-1 and U266, had relative resistance index values of 2 or more to some of the drugs, but not to the others, and 19 other cell lines did not. These results indicate that the reactivity of MRK16-F(ab')₂ correlates with a relative resistance index of 2 or more to all these drugs in cultured human leukemia and lymphoma cell lines.