Showing papers in "Japanese Journal of Cancer Research in 1988"
TL;DR: A case‐control study of gastric cancer was done in a rural area of northern Kyushu, Japan, in relation to dietary habits especially focusing on the relationship with the consumption of broiled fish, and consistently in the comparisons with both sets of controls, the risk of gastrics cancer was inversely related with the Consumption of fruits and positively associated with cigarette smoking.
Abstract: A case-control study of gastric cancer was done in a rural area of northern Kyushu, Japan, in relation to dietary habits especially focusing on the relationship with the consumption of broiled fish. The study was based upon 139 cases of newly diagnosed gastric cancer at a single institution, 2,574 hospital controls and 278 controls sampled randomly from the residents of the study area (with sex and year of birth matched). No association was observed between the consumption of broiled fish and gastric cancer risk whether three types of broiled fish (raw fish, dried fish and salted fish) were analyzed separately or as a single category. However, consistently in the comparisons with both sets of controls, the risk of gastric cancer was inversely related with the consumption of fruits and positively associated with cigarette smoking. A decreased risk of gastric cancer was also noted among those with high consumption of green tea (10 or more cups per day).
282 citations
TL;DR: A nucleic acid‐rich fraction extracted and purified from BCG (MY‐1) augmented natural killer cell activity of mouse spleen cells in vitro, and produced factor(s) which showed anti‐viral activity and rendered normal macrophages cytotoxic towards tumor cells.
Abstract: A nucleic acid-rich fraction extracted and purified from BCG (MY-1) augmented natural killer (NK) cell activity of mouse spleen cells in vitro, and produced factor(s) which showed anti-viral activity and rendered normal macrophages cytotoxic towards tumor cells. These cellular responses were induced by the MY-1 digested preliminarily with RNase, but not by the MY-1 digested with DNase, indicating that DNA contained in MY-1 was essential for the responses. The function of the factor to activate macrophages was destroyed by treatment with a small amount of anti-interferon (IFN)-gamma antiserum or under acidic conditions (pH 2), but not by treatment with anti-IFN-alpha/beta antiserum, while the anti-viral activity was destroyed almost completely by treatment with anti-IFN-alpha/beta antiserum. It appears that DNA from BCG stimulated mouse spleen cells in vitro, resulting in augmentation of NK activity and production of IFN-alpha/beta and -gamma.
237 citations
237 citations
TL;DR: The present work on tumor vascular permeability has led to the following findings, which confirmed that kinin is generated via the kallikrein‐dependent cascade in the ascitic tumor fluid and blocked this kinin‐generating cascade with Kunitz‐type soybean trypsin inhibitor, and the formation of ascites was suppressed.
Abstract: Enhanced vascular permeability in tumor tissue has profound pathological consequences in tumor biology. However, details of the mechanism involved are not clear. The present work on tumor vascular permeability has led to the following three findings. (i) Ascitic tumor fluid contained kinin (about 1-40 ng/ml), which is known to enhance vascular permeability and induce pain in vivo. (ii) Kinin is generated via the kallikrein-dependent cascade in the ascitic tumor fluid. By blocking this kinin-generating cascade with Kunitz-type soybean trypsin inhibitor the formation of ascites was suppressed. (iii) Blocking of kinin-degrading enzymes (kininases I and II) by an appropriate kininase inhibitor (e.g., captopril) may result in increased permeability, leading to accumulation of the ascitic fluid. This phenomenon was verified by an about 1.2-1.5 fold increase in leakage of 51Cr-labeled bovine serum albumin into the ascites when kininase inhibitors had been administered orally 30 min before intravenous administration of the bovine serum albumin.
150 citations
TL;DR: Dinophysistoxin‐1 showed a tumor‐promoting activity as strong as that of okadaic acid in a two‐stage carcinogenesis experiment on mouse skin and acted on cells through different pathways from the 12‐O‐tetradecanoylphorbol‐13‐acetate‐type tumor promoters.
Abstract: Dinophysistoxin-1, 35-methylokadaic acid, is a causative agent of diarrhetic shellfish poisoning. The biological activities and tumor-promoting activity of dinophysistoxin-1 were studied together with those of okadaic acid and 7-O-palmitoyl okadaic acid. Dinophysistoxin-1 is a skin irritant and induces ornithine decarboxylase in mouse skin with the same potency as okadaic acid. 7-O-Palmitoyl okadaic acid induced a lower activity than the other compounds. Dinophysistoxin-1 inhibited the specific [3H]okadaic acid binding to a particulate fraction of mouse epidermis. The binding affinities of dinophysistoxin-1 and okadaic acid to a particulate fraction were almost the same. Dinophysistoxin-1 showed a tumor-promoting activity as strong as that of okadaic acid in a two-stage carcinogenesis experiment on mouse skin. The percentages of tumor-bearing mice in the groups treated with 100 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA) followed by 5 micrograms of dinophysistoxin-1, twice a week, and with DMBA followed by 5 micrograms of okadaic acid twice a week were 86.7% and 80.0% in week 30, respectively. The average number of tumors per mouse was 4.6 in the former group and 3.9 in the latter. Dinophysistoxin-1 and okadaic acid act on cells through different pathways from the 12-O-tetradecanoylphorbol-13-acetate-type tumor promoters.
128 citations
124 citations
TL;DR: LEC rats seem to be a promising animal model for studying the pathogenesis of hepatitis and hepatocellular carcinoma, as they had no normal tissue and showed chronic hepatitis in nontumorous tissues of the liver.
Abstract: A remarkably high incidence of hepatocellular carcinomas was observed in long-surviving LEC rats with hereditary hepatitis. Among the 60 LEC rats examined between 12 and 28 months of age from F29, and F30, 55 (92%) developed putative preneoplastic and neoplastic lesions such as hyperplastic foci and nodules, and hepatocellular carcinomas. Of these, hepatocellular carcinomas were observed with a high frequency (46/55; 84%). All rats of advanced age that survived more than 18 months developed hepatocellular carcinomas. These results suggest that the development of liver tumors in LEC rats is an age-associated phenomenon with serial hepatic alterations after the subsidence of acute hepatitis. The long-surviving rats had no normal tissue and showed chronic hepatitis in nontumorous tissues of the liver. Cholangiofibrosis was also found in most rats with hepatic lesions. Metastasis of hepatocellular carcinomas was found in four rats. Histologically, the hepatocellular carcinomas were of a well-differentiated type with a typical trabecular structure. Thus, LEC rats seem to be a promising animal model for studying the pathogenesis of hepatitis and hepatocellular carcinoma.
116 citations
TL;DR: Direct cytotoxicity of poly(dG, dC) at a concentration of 1,000 μg/ml against IMC cells was not observed in vitro, and the virus‐inhibitory activity of the supernatant was mostly neutralized by anti‐IFNα/β.
Abstract: When various synthetic double- or single-stranded DNAs were incubated with spleen cells from mice (BALB/c or CDF1) at 37° for 20 hr, it was found that some of the DNAs augmented NK activity and produced factors in the culture supernatants which showed antiviral activity and activity to render mouse macrophages cytotoxic toward tumor cells. Poly(dG, dC) showed the strongest activities, when incubated with spleen cells from lipopolysaccharide-nonresponsive mice, C3H/HeJ. The activity of the culture supernatant to activate macrophages was completely abolished by a small amount of anti-IFNγ antibody. On the other hand, the virus-inhibitory activity of the supernatant was mostly neutralized by anti-IFNα/β. When IMC tumor cells (5 × 105 cells) were mixed with poly(dG, dC) (100 μg) and then inoculated intradermally into CDF1 mice, the tumor did not take, while tumors grew progressively and killed the mice in a control group inoculated with tumor cells alone. Direct cytotoxicity of poly(dG, dC) at a concentration of 1,000 μg/ml against IMC cells was not observed in vitro.
96 citations
TL;DR: Results indicate that low levels of GST π mRNA expression in SCLC cell lines inversely correlate to high sensitivity to cisplatin and carboplatin, and suggest that GSTπ may play an important role in intracellular inactivation of these drugs.
Abstract: The amounts of mRNA for glutathione S transferase pi (GST pi) were significantly lower in 3 human small cell lung cancer (SCLC) cell lines than in 3 non small cell lung cancer (NSCLC) cell lines. The sensitivities of the 3 SCLC cell lines to cisplatin and carboplatin were much higher than those of the 3 NSCLC cell lines. These results indicate that low levels of GST pi mRNA expression in SCLC cell lines inversely correlate to high sensitivity to cisplatin and carboplatin, and further suggest that GST pi may play an important role in intracellular inactivation of these drugs.
84 citations
TL;DR: Acquisition of high multidrug resistance in VJ‐300 might be correlated with both activated transcription of mdr‐1 gene and amplification.
Abstract: A multidrug-resistant clone of human cancer KB cells was isolated by stepwise selection on exposure to increasing doses of vincristine. The final clone, VJ-300, obtained after ethylmethane sulfonate mutagenesis showed 400-fold higher resistance to vincristine than did KB cells. Cellular accumulation of vincristine in VJ-300 was decreased to less than one-tenth of that in KB. The cells were also cross-resistant to daunomycin, adriamycin, actinomycin D, colchicine and VP-16. During continuous culturing in the absence of any drug for several months, a different colchicine-resistant and multidrug-resistant clone, KB-C1, reverted almost completely to drug sensitivity, whereas drug resistance in VJ-300 was stably maintained. Amplification of the multidrug-resistance-1 (mdr-1) gene was more than 20-fold in KB-C1, but less than 2-fold in VJ-300. mdr-1 mRNA was, however, expressed in VJ-300 at a rate comparable to KB-C1. Acquisition of high multidrug resistance in VJ-300 might be correlated with both activated transcription of mdr-1 gene and amplification.
82 citations
TL;DR: In tumor‐bearing mice, pretreatment with BSN did not affect the antitumor activity of ADR, although its cardiotoxicity was significantly depressed, and the ability of BSN to reduce specifically the toxicity ofADR may be ascribed to the fact that Bi induces MT in the target tissue of ADr toxicity but not in a tumor.
Abstract: The effect of preinduction of metallothionein (MT) by bismuth (Bi) compounds on the toxic side effects and antitumor activity of adriamycin (ADR) was investigated in mice. Preinduction of MT by oral administration of bismuth subnitrate (BSN) significantly decreased the lethal toxicity, cardiotoxicity and bone marrow toxicity observed with a single subcutaneous injection of ADR. A significant increase in the concentration of cardiac MT was observed in mice treated with BSN. The MT level in the heart was significantly correlated with the protective effect of BSN against the cardiotoxicity of ADR. In tumor-bearing mice, pretreatment with BSN did not affect the antitumor activity of ADR, although its cardiotoxicity was significantly depressed. The ability of BSN to reduce specifically the toxicity of ADR may be ascribed to the fact that Bi induces MT in the target tissue of ADR toxicity but not in a tumor. The protective effect of MT against the toxicity of ADR, which is believed to act as an anticancer agent by generating active oxygen, can be assumed to be due to its ability to scavenge free radicals or inhibit their formation.
TL;DR: The results strongly suggest that the increase in EGF receptor levels may be associated with the development of human squamous cell cancers of esophagus and lung.
Abstract: The levels of epidermal growth factor (EGF) receptors were investigated in surgically resected tumors of various origins including esophagus (n = 33), lung (n = 14), pancreas (n = 9), colorectum (n = 10), breast (n = 23) and stomach (n = 8). The 125I-EGF binding capacities of squamous cell carcinomas of esophagus and lung were exceptionally higher than those of the other cancer tissues. Immunohistochemical staining with an anti-EGF receptor monoclonal antibody detected EGF receptors in the basal cells and parabasal cells of normal esophageal epithelium and in all the cancer cells of squamous cell carcinoma tissues of esophagus and lung. DNA replicating cells were examined by the bromodeoxyuridine staining method and it was found that the basal cells and parabasal cells of normal epithelium and peripheral cells of cancer pearls are proliferating. Contrary to this, a tumor antigen TA-4, known as a specific marker for squamous carcinoma, was detected in the differentiated cancer cells and in middle-layer squamous cells. These results strongly suggest that the increase in EGF receptor levels may be associated with the development of human squamous cell cancers of esophagus and lung. Thus, measurement of EGF receptor expression in tumor tissues has diagnostic value and should prove useful for the development of new therapies.
TL;DR: The hst‐1 gene, previously designated the hst gene, was identified as a transforming gene by transfection assays of genomic DNAs from various types of human cancers by indicating close chromosomal localization of the two genes, which were amplified as one amplification unit.
Abstract: The hst-1 gene, previously designated the hst gene, was identified as a transforming gene by transfection assays of genomic DNAs from various types of human cancers. We analyzed for alterations of the hst-1 gene in 18 bladder cancers, 23 renal cell carcinomas and 5 esophageal cancers. Although rearrangement of the gene was not detected in any of these samples, amplification of the hst-1 gene was found in 4 samples of tumors, including an invasive bladder cancer, both primary esophageal cancer and its lymph node metastasis, and kidney metastasis of an esophageal cancer. The same degree of amplification of the int-2 gene, the product of which has significant homology with the hst-1-encoded protein, was also observed in all of these DNA samples with amplified hst-1 gene. This result indicates close chromosomal localization of the two genes, which were amplified as one amplification unit.
TL;DR: Electrolysis of ellagic acid inhibited the hepatocarcinogenesis induced by FAA when it was administered concurrently with the carcinogen.
Abstract: The effect of ellagic acid (EA) on the hepatocarcinogenesis induced by N-2-fluorenylacetamide (FAA) was investigated in male ACI/N rats Rats were fed diet containing 200 ppm FAA and 400 ppm EA for 16 weeks, and diet containing 400 ppm EA alone was fed to the animals for one week before FAA exposure and one week after the carcinogen treatment Animals were killed at intervals up to 20 weeks after cessation of the carcinogen Liver altered foci and neoplasms were quantified using gamma-glutamyl transpeptidase reaction as well as conventional staining for identification Exposure to FAA alone induced a substantial number of altered foci and at the end of experiment (week 36), the incidence of hepatocellular neoplasms was 100% In the group receiving EA together with FAA, the number of altered foci was decreased at all time points and at termination, the final incidence of hepatocellular neoplasms (30%) was also reduced Thus, EA inhibited the hepatocarcinogenesis induced by FAA when it was administered concurrently with the carcinogen
TL;DR: The transformation frequency of mouse BALB/3T3 cells was significantly enhanced after transfection with an activated ras oncogene followed by treatment with a tumor promoter, 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA), suggesting that the rasoncogene acted as an initiator in two‐stage carcinogenesis.
Abstract: The transformation frequency of mouse BALB/3T3 cells was significantly enhanced after transfection with an activated ras oncogene (v-Ha-ras) followed by treatment with a tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), suggesting that the ras oncogene acted as an initiator in two-stage carcinogenesis. A cell clone (Bhas42) containing the ras oncogene was isolated from the ras-transfected BALB/3T3 cells. Bhas42 cells were flat and showed contact inhibition, but the addition of TPA to quiescent Bhas42 cultures resulted in a dramatic change of cell morphology to spindle shape, doubling of the cell population, and increased DNA synthesis.
TL;DR: BHT is found to be tumorigenic to the liver of the B6C3F1 male mouse, and the incidence of mice with either a hepatocellular adenoma or a focus of cellular alteration in the liver was increased in a clear dose‐response relationship.
Abstract: Butylated hydroxytoluene (BHT), a preservative widely found in food as a food additive, was orally administered at concentrations of 1% and 2% of the diet to B6C3F1 mice for 104 consecutive weeks Treated animals underwent a 16-week recovery period prior to pathological examination In male mice administered BHT, the incidence of mice with either a hepatocellular adenoma or a focus of cellular alteration in the liver was increased in a clear dose-response relationship The incidences of male mice with other tumors and the incidences of female mice with any tumor were not significantly increased as a consequence of BHT administration The results of this study indicate BHT to be tumorigenic to the liver of the B6C3F1 male mouse
TL;DR: Gangliosides were shown to bear the tumor‐associated N‐glycolylneuraminic acid (NeuGc)‐specific Hanganutziu‐Deicher (HD) antigen expressed in human retinoblastoma cells.
Abstract: Gangliosides were shown to bear the tumor-associated N-glycolylneuraminic acid (NeuGc)-specific Hanganutziu-Deicher (HD) antigen expressed in human retinoblastoma cells. HD antigenic gangliosides were detected by thin-layer chromatography/enzyme-immunostaining using affinity-purified chicken antibody against GM3 containing NeuGc and horseradish peroxidase-conjugated anti-chicken IgG. One to four species of the antigenic gangliosides were detected from all of 4 cell lines, Y79, WERI-Rb1, TOTL1, and YK, as well as freshly cultured retinoblastoma cells and isolated tumor tissue. All cases contained GM3(NeuGc) as an HD antigen. No HD antigenic ganglioside was detected in normal retinal tissues by the same procedure.
TL;DR: An HTLV‐I‐transformed T cell line, obtained from the peripheral blood of a virus‐infected F1 rabbit, was able to kill syngeneic newborn rabbits within 7 days, when inoculated intraperitoneally at a dose of 1 × 108 cells.
Abstract: An HTLV-I-transformed T cell line, obtained from the peripheral blood of a virus-infected (B/J × Chbb:HM) F1 rabbit, was able to kill syngeneic newborn rabbits within 7 days, when inoculated intraperitoneally at a dose of 1 × 108 cells. Inoculation of 1 × 107 cells killed or rendered moribund 50% of inoculated animals, while surviving animals exhibited cell-mediated cytotoxic activities against the transformed cells. The peripheral blood leukocyte counts increased in all surviving animals, in association with appearance of abnormal lymphocytes with convoluted or lobulated nuclei. Pathological examination of animals that died one week post-inoculation revealed no tumors in the abdominal cavity, but accumulation of ascites containing abnormal lymphocytes. Histological examination showed leukemic infiltration in the liver, lungs, spleen and mesenteric lymph nodes. The same cell line was also able to kill syngeneic adult rabbits in 8–10 days when inoculated intravenously, but not intraperitoneally, at a dose of 1 × 108 cells. Leukemic infiltration was observed in the major organs of these animals. Adult animals which were already virus carriers were resistant to this lethal inoculation. This rabbit ATL-like disease may prove to be useful as an experimental model for acute adult T cell leukemia.
TL;DR: The presently described approach appears promising for development of medium‐term bioassay systems for detection of environmental carcinogens.
Abstract: Two wide-spectrum initiation models were investigated in F344 male rats. Model I: After sequential treatment with diethylnitrosamine (DEN), N-methylnitrosourea (MNU) and dihydroxy-di-N-propylnitrosamine (DHPN), animals were given phenobarbital (PB) or N, N-dibutylnitrosamine (DBN) as a test compound for 14 weeks and sacrificed at week 18. Model II: Animals were treated with DHPN, followed by N-ethyl-N-hydroxyethylnitrosamine (EHEN), and then 3,2′-dimethyl-4-aminobiphenyl (DMAB) as initiators and were subsequently given 3-methylcholanthrene (MCA) or PB as a test compound for 11 weeks. Animals were sacrificed 16 weeks after the commencement. In both models, assessment of lesion yield revealed significant enhancement of carcinogenesis by the test compounds in their respective target organs. Since, in many cases, treatment with PB, DBN and MCA subsequent to the combined initiation procedures brought about a marked increase in lesion development, far greater than a simple sum of the yields given by initiators and test compounds alone, the presently described approach appears promising for development of medium-term bioassay systems for detection of environmental carcinogens.
TL;DR: The bindings of the three retinoids (RA, Am80 and Ch55) to RSBP greatly enhanced the affinity of R SBP for the nuclei, and strongly support the idea that RSBp is the true receptor of retinoid.
Abstract: The uptake of all-trans-retinoic acid (RA) and two new retinoids [4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbamoyl )benzoic acid (Am80) and (E)-4-[3-(3,5-di-tert-butylphenyl)-3-oxo-1-propenyl]benzoic acid (Ch55)] by HL-60 human promyelocytic leukemia cells was investigated. For the investigation, [3H]RA and [3H]Am80 with high specific radioactivities (more than 50 Ci/mmol) were used. [3H]Am80 was prepared by hydrogenolysis of the corresponding chlorinated derivative of Am80 with tritium gas. The retinoids RA, Am80 and Ch55 were efficiently taken up by HL-60 cells, and induced differentiation of the cells into mature granulocytes. The specific bindings (uptake) of RA, Am80 and Ch55 (the bindings inhibited competitively by the other two retinoids) by HL-60 cells were due to a newly detected binding protein. The protein that bound specifically to RA appeared identical to that which bound specifically to Am80 by high-performance liquid chromatography (HPLC), and was named retinoid-specific binding protein (RSBP). One HL-60 cell was found to contain about 1500 molecules of RSBP distributed between the nuclear fraction and cytosolic fraction in proportions of about 4:1. The bindings of the three retinoids (RA, Am80 and Ch55) to RSBP (i.e., formation of retinoid-RSBP complexes) greatly enhanced the affinity of RSBP for the nuclei. The apparent molecular weight of RSBP was estimated to be 95,000 daltons by size exclusion HPLC. The association constants (Ka) of RSBP were calculated to be 2.4 X 10(10) M-1 for RA and 4.4 X 10(10) M-1 for Am80 from Scatchard plots. The bindings of RA, Am80 and Ch55 to RSBP were mutually competitive, indicating that the binding sites for RA, Am80 and Ch55 were identical. The very high affinities of these retinoids for RSBP (Ka's of the order of 10(10) M-1) correspond to the effective concentrations of these retinoids in HL-60 cell culture medium for induction of differentiation of the cells. The mutually competitive bindings of these retinoids strongly support the idea that RSBP is the true receptor of retinoids.
TL;DR: The hst‐1 gene, previously designated as the hst gene, and seven other oncogenes were examined for possible structural changes in esophageal, gastric and colorectal carcinomas by Southern blot hybridization.
Abstract: The hst-1 gene, previously designated as the hst gene, and seven other oncogenes were examined for possible structural changes in esophageal, gastric and colorectal carcinomas by Southern blot hybridization. The hst-1 gene was amplified in eight (42.1%) of the nineteen esophageal squamous cell carcinomas and in all four metastatic tumors of lymph nodes. The degree of amplification ranged from two to eight times. Coamplification of the hst-1 and c-erbB-1 gene was found in one case of esophageal carcinoma. However, no amplification of the hst-1 gene was detected in gastric and colorectal carcinomas.
TL;DR: In high‐performance liquid chromatography, formation of N‐hydroxy‐Glu‐P‐1 was detected and accounted for more than 80% of the total mutagenicity observed in the human microsomal system with Glu‐ P‐1, indicating that, similarly to experimental animals, N‐Hydroxylation is a major activating step for heterocyclic arylamines in human.
Abstract: Metabolic activating capacity of human livers for carcinogenic heterocyclic arylamines has been studied using a Salmonella mutagenesis test. A large individual variation was observed among 15 liver samples in the capacities of activation of Glu-P-1(2-amino-6-methyldipyrido[1,2-α:3′,2′-d]imidazole), IQ (2-amino-3-methylimidazo[4,5-f]quinoline) and MeIQx (2-amino-3,8-dimethyl-3H-imidazo[4,5-f]quinoxaline). The average numbers of revertants induced by the three heterocyclic arylamines were nearly the same or rather higher in the presence of hepatic microsomes from human than those from rat. In high-performance liquid chromatography, formation of N-hydroxy-Glu-P-1 was detected and accounted for more than 80% of the total mutagenicity observed in the human microsomal system with Glu-P-1, indicating that, similarly to experimental animals, N-hydroxylation is a major activating step for heterocyclic arylamines in human. Addition of flavone or 7,8-benzoflavone to human liver microsomes showed effective inhibition of the mutagenic activation of Glu-P-1, although the treatment rather enhanced microsomal benzo[a]pyrene hydroxylation in human livers. Mutagenic activation of Glu-P-1 by human liver microsomes was also decreased by the inclusion of anti-rat P-448-H IgG, and was well correlated with the content of immunoreactive P-448-H in livers, suggesting the involvement of a human cytochrome P-450, which shares immunochemical and catalytic properties with rat P-448-H, in the metabolic activation of heterocyclic arylamines in human livers.
TL;DR: Results suggest that PTHrP plays an important role in developing the hyperealcemia frequently observed in ATL patients.
Abstract: Human parathyroid hormone-related protein (PTHrP) mRNA was detected in peripheral leukemic cells obtained from adult T-cell leukemia (ATL) patients as well as in cultured human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines. In contrast, PTHrP mRNA was not detected in other types of leukemic cells. Using radioimmunoassay, immunoreactive PTHrP was also detected in the spent media of HTLV-I-infected T-cell lines. These results suggest that PTHrP plays an important role in developing the hypercalcemia frequently observed in ATL patients.
TL;DR: The results suggest that the antitumor effects of most anti-tumor agents are over‐ or underestimated in this model when MTD's are used as a therapeutic dose, and indicate that the use of clinically equivalent doses determined pharmacokinetically isdesirable.
Abstract: To improve clinical predictability from therapeutic results of various antitumor agents in human tumor/nude mouse models it seems to be important to use a dose pharmacokinetically equivalent to the clinical dose. Thus, we attempted to find the dose of a given drug that can reproduce in the nude mouse a plasma level similar to that seen in human patients treated with an effective dose of the drug based on comparative pharmacokinetic studies between man and nude mouse. As a result, those of 3 alkylating agents, mitomycin C, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) and cyclophosphamide, and those of 2 antimitotic agents, vincristine and vinblastine, were estimated to be one-fourth or one-fifth of their maximum tolerated doses (MTD's). On the other hand, in the case of adriamycin, its MTD was approximately equivalent to its clinical dose pharmacokinetically. In contrast, clinically equivalent doses of 2 antimetabolites tested, 5-fluorouracil and methotrexate, were significantly greater than their MTD's; i.e., their plasma levels did not reach the effective clinical ones even when their MTD's were administered to the nude mice. These results suggest that the antitumor effects of most antitumor agents are over- or underestimated in this model when MTD's are used as a therapeutic dose, and indicate that the use of clinically equivalent doses determined pharmacokinetically is desirable.
TL;DR: The results suggest that the simultaneous screening method, based on the synthesis of radiolabeled cDNA corresponding to the mRNA population of malignant cells and on hybridization with various oncogene probes, immobilized on a membrane filter, can be used to examine the overexpression of oncogenes.
Abstract: Abnormal expression of various oncogenes has been implicated in the development of many malignant tumors. Although RNA blotting methods have been used to measure abnormal expression, they involve the time-consuming process of individually labeling the oncogene probes. To simplify this process we have attempted to develop a new method, termed simultaneous screening, which is based on the synthesis of radiolabeled cDNA corresponding to the mRNA population of malignant cells and on hybridization with various oncogene probes, immobilized on a membrane filter. This method circumvents the time-consuming process of the prevailing RNA blotting methods and is also sensitive enough to detect accurately a five- to ten-fold level of expression of rare mRNA (∼10 copies per cell). Overexpression of ten oncogenes was detected in a variety of malignant cells and mitogen-stimulated cells with this method. These results suggest that our simultaneous screening method can be used to examine the overexpression of oncogenes.
TL;DR: Results suggest that the liver cell foci are potential precursors of HCC in WHV‐infected animals, and that serum GGT may be a useful marker for indicating the development of carcinoma.
Abstract: The histochemical characteristics of liver cell foci in woodchucks were investigated. The foci appeared to be distributed throughout the liver and were observed only in the woodchuck hepatitis virus (WHV)-positive animals, including all 19 woodchucks with hepatocellular carcinoma(HCC), and 7 without HCC. No foci appeared in 11 WHV-negative animals. Histochemical studies revealed that liver cell foci and carcinoma cells were characterized by positive gamma-glutamyl transpeptidase (GGT) enzymatic reactions and decreased glucose-6-phosphatase enzyme activity compared to non-neoplastic liver. Furthermore, serum GGT was significantly elevated in almost all of the animals which had larger carcinomas. Ultrastructural findings of foci showed some resemblance to carcinoma cells, being characterized by abundant free ribosomes within the cytoplasm and undeveloped endoplasmic reticulum. These results suggest that the liver cell foci are potential precursors of HCC in WHV-infected animals, and that serum GGT may be a useful marker for indicating the development of carcinoma.
TL;DR: Cloning of T lymphocytes lacking the HGPRT activity using recombinant IL2 (rIL2) and observed an increased frequency of somatic mutation in poison gas workers who had had more chances to be exposed to mustard gas and those who had worked for a longer period suggested that inhalation of small amounts of mustard gas damaged somatic cell genes, resulting in carcinogenesis.
Abstract: The former workers at the Okunojima poison gas factory comprise a high risk group for malignant tumors such as respiratory tract cancer. Demonstration of injury to somatic cell genes in this group may provide important data for evaluating the association between mustard gas and malignant tumors. So we measured the frequency of T lymphocytes lacking the hypoxanthine guanine phosphoribosyl transferase (HGPRT) activity, by cloning with interleukin 2 (IL2). In this study, we performed cloning of T lymphocytes lacking the HGPRT activity using recombinant IL2 (rIL2) and observed an increased frequency of somatic mutation in poison gas workers who had had more chances to be exposed to mustard gas and those who had worked for a longer period. This result suggested that inhalation of small amounts of mustard gas damaged somatic cell genes, resulting in carcinogenesis.
TL;DR: Daily meat consumption was significantly associated with the occurrence of ovarian cancer even after adjusting for reproductive and other risk factors by conditional logistic regression analysis, which might explain the rise of the mortality rate among the Japanese elderly.
Abstract: The age-specific mortality rate of ovarian cancer is increasing among women over 50 years of age, but remaining at a stable level among women under 50. This case-control study of ovarian cancer was undertaken to assess the environmental factors which may increase the mortality of the disease in the elderly. Fifty-six women with primary epithelial ovarian cancer whose ages were 50 years old or over were compared with two age-matched control groups. The results of the Mantel-Haenszel analysis were as follows. More cases were found to have never married than controls (P less than 0.05), a larger proportion of cases were nulliparous (P less than 0.05), a smaller proportion of cases had experienced an induced abortion (P less than 0.05) or had undergone permanent sterilization by tubal ligation (P less than 0.05), the occurrence of breast or uterine cancer was more common in the mother or sisters of cases (P less than 0.01), a larger percentage of cases used to eat meat daily (P less than 0.01) or used to eat fish daily (P less than 0.05), and a larger proportion of cases weighed under 40 kg (P less than 0.05). Daily meat consumption was significantly associated with the occurrence of ovarian cancer even after adjusting for reproductive and other risk factors by conditional logistic regression analysis. The attributable risk for ovarian cancer in the elderly was 19.2% for daily meat consumption. The recent change in dietary habits might in part explain the rise of the mortality rate among the Japanese elderly.
TL;DR: In this article, differences in the pattern of lung cancer histology and related time trends between Osaka, Japan, and the North West Region of England were investigated to find a clue to lung cancer etiology in Japan.
Abstract: To find a clue to lung cancer etiology in Japan, differences in the pattern of lung cancer histology and related time trends between Osaka, Japan, and the North West Region of England were investigated. Material comprised all incident lung cancer cases registered in both regional registries (14,521 in the Osaka Cancer Registry and 29,859 in the North West Regional Cancer Registry). (1) The age-standardized incidence rate of lung cancer was higher in the North West Region than in Osaka (80.4 among males and 20.9 among females per 100,000 population in 1979-82 versus 32.1 and 9.2 respectively). (2) A higher proportion of adenocarcinoma was observed in Osaka (36.3% in males and 62.0% in females) than in the North West Region (12.3% and 18.9% respectively). (3) Using the relative frequencies of each histological type according to sex and age-group, age-standardized incidence rates were calculated for the main lung cancer histological types. It was shown that the incidence rates of adenocarcinoma were similar in the two areas (10.6 in males and 5.3 in females in Osaka versus 10.0 and 3.5 in the North West Region, respectively) while those of squamous cell and small cell carcinomas were much higher in the North West Region than in Osaka. (4) Time trends of incidence rates showed an increase only for adeno- and small cell carcinomas in Osaka. Slight increases were observed for adenocarcinoma in both sexes and for squamous cell carcinoma in females in the North West Region. (5) Considering cigarette consumption and the relative risks of smoking in the two areas, the possible existence of other risk factors for adenocarcinoma in both sexes in Japan, besides active smoking, was suggested.