Augmentation of human immunodeficiency virus (HIV) replication in cells infected with HTLVs has been demonstrated by cellular biological studies. Here, evidence is presented that this effect could be ascribed, at least in part, to the level of HIV gene expression.
Since loss of genes on the short arm of chromosome 11 (11p) is known to be closely associated with several human tumors, we analyzed DNA of lung carcinomas from 45 patients with respect to loss of heterozygosity at loci on 11p. We observed that loss of heterozygosity at 11p loci was quite frequent (17 of 41 informative cases, 41%) and it appeared that the loss might be associated with more advanced carcinomas than those of stage Ia. In many cases, sequences at the CAT and/or the D11S12-IGF2 loci were commonly deleted. These observations suggest that loss of genes at particular regions on 11p might be involved in progression of human lung carcinomas.
GM2 ganglioside was detected in all five sera of hepatoma patients analyzed by thin-layer chromatography in conjunction with enzyme-immunostaining with rabbit anti-GM2 antibody and horseradish peroxidase-conjugated anti-rabbit IgG, and was quantitated by densitometry. The GM2 contents of these sera were 20 to 100 times higher than those of sera from normal adults. By the method used, an increased GM2 level could be detected with samples of less than 0.1ml of sera from hepatoma patients. The elevated levels of serum GM2 in hepatoma patients were suggested to be due to elevated GM2 levels in the liver lesions, because the GM2 contents of the liver of five patients with liver cancer, including three with hepatoma, were higher than those of normal liver tissues.
Four murine monoclonal antibodies (NCC-RAS-001, -004, -005, -017) reactive with ras p21 were produced by using recombinant c-Ha-ras p21 as an immunogen. Among these antibodies, NCC-RAS-004 was extremely sensitive when used in immunoblotting analysis, facilitating semiquantitative detection of c-Ha-, c-Ki- and N-ras p21 in cell and tissue lysates. In cells carrying a point-mutationally activated ras, p21 with abnormal mobility upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis was clearly detected.
Application of a high-voltage electrical impulse (5kV/cm, 2msec) after bleomycin administration resulted in a significant size decrease of subcutaneously inoculated AH-109A hepatocellular carcinoma in Donryu rats. The tumor size decreased to an average of 17% of the initial mass 4 days after the treatment. Neither the high-voltage electrical impulse nor bleomycin administration alone showed an inhibitory effect on the tumor growth. It was concluded that the concomitant use of a high-voltage electrical impulse and an anticancer drug has the potential to be applicable for cancer treatment.
Mortalities from selected sites of cancer among 5, 130 male Japanese physicians followed up for 19 years were examined in relation to smoking and drinking habits surveyed in 1965. With smoking habit classified into three categories (never/past, 1-19 and_??_20 cigarettes/day) and drinking habit into four (never/past, occasional, <2 and_??_2 go of sake/day), the effects of the two factors and their combined effect were analyzed by using the Cox proportional hazard model. Interaction of smoking and drinking was found to be negligible for the sites of cancer studied (upper aerodigestive tract, esophagus, stomach, large bowel, liver and lung), and independent relationships of smoking and drinking with upper aerodigestive cancer were confirmed. Smoking, besides being strongly associated with lung cancer, was also weakly, but significantly, related to stomach cancer. Liver cancer showed no association with smoking whereas this cancer was significantly related to alcohol consumption. The present findings provide further evidence for the association between cigarette smoking and stomach cancer but do not support the relationship recently suggested between smoking and liver cancer.
As a typical autoimmune disease, chronic thyroiditis may impose unusual risks for malignancies. A long-term follow-up study of a large number of patients (4, 531) with chronic thyroiditis at the Noguchi Hospital in Ooita Prefecture was conducted for 0-24 years, the objective being to assess risks for various sites of neoplasms by comparing the observed numbers of deaths with the expected numbers computed from the mortality rates in Japan. There was no increase in risk for overall malignancies (90 observed vs. 104.1 expected) or breast cancer (4 observed vs. 5.7 expected). The patients had an increased risk for myelo-and lympho-proliferative neoplasms (13 observed vs. 4.9 expected, P<0.01), as found in a few previous follow-up studies. A new and unexpected finding was that the patients showed decreased risk for cancers of digestive tract (24 observed vs. 44.3 expected, P<0.01). The reason for this decline could not be elucidated in this study, so that further epidemiological studies and animal experiments in this respect are needed.
The effect of 1000ppm potassium perchlorate (KClO4), 1000ppm potassium iodide (KI) or 1000ppm propylthiouracil (PTU) in the diet on the development of thyroid tumors was studied histologically and biochemically in Wistar rats given a single ip injection of 280mg of N-bis (2-ydroxypropyl) nitrosamine (DHPN) per 100g body weight. Basal diet containing 1000ppm KClO4, 1000ppm KI or 1000ppm PTU was given for 19 weeks from week 2 to week 20. The incidence of thyroid adenomas at the end of week 20 of the experiment was 100% (20/20) in rats treated with DHPN followed by KClO4, 85% (17/20) in rats given DHPN followed by KI, 95% (19/20) in rats given DHPN followed by PTU, and 5% (1/20) in rats given DHPN alone. The incidence of thyroid cancers was 100% (20/20) in rats treated with DHPN followed by KClO4, 65% (13/20) in rats treated with DHPN followed by KI and 0% (0/20) in rats treated with DHPN followed by or not followed by PTU. Rats given KClO4, KI or PTU alone and untreated rats had no thyroid tumors. The mean values of TSH in serum were 2.94±0.79ng/ml in rats treated with DHPN followed by KClO4, 9.40±16.0ng/ml in rats treated with DHPN followed by KI and 60.94±20.60ng/ml in rats treated with DHPN followed by PTU. It was confirmed that (1) KClO4, PTU and KI promote the development of thyroid tumor in rats treated with DHPN, (2) the promoting effect of KClO4, or KI is stronger than that of PTU and (3) the value of TSH in serum is not parallel to the promoting effect on the development of thyroid tumor.
The human hepatoma cell line, huGK-14, containing integrated hepatitis B virus (HBV) DNAs, produced a large number of 23nm spherical particles of HBV surface antigen (HBsAg) in a serum-free medium. These particles closely resembled the HBsAg particles found in the sera of HBV carriers and elicited a high antibody response in guinea pigs. The huGK-14 cells in a serum-free medium would provide a new, economic source of HBV vaccine.
This study was performed to estimate human T-cell leukemia-lymphoma virus type-I (HTLV-I) infection and human immunodeficiency virus (HIV) infection in Japanese immigrant colonies in Bolivia, where no seroepidemiological study of HTLV-I or HIV has ever been reported, among 647 healthy adults and children of Japanese descent and Bolivian natives living in the same colonies. The overall prevalence of HTLV-I antibody was 12.6% (59/469) among Japanese immigrant populations, but increased with age, being 16.2% (49/303) among adults and 6.0% (10/166) among children; no significant difference in relation to sex was noted. The first generation immigrants (issei) from Kyushu, the large southwestern island of Japan where adult T-cell leukemia (ATL) is endemic, had 19.0% (49/258) HTLV-I seroprevalence, while issei from outside Kyushu had none (0/39). Among Bolivian members of the community, consisting mostly of Indians and persons of Spanish descent, the HTLV-I seroprevalence was 4.3% (7/164) overall, 2.4% (1/42) among adults and 4.9% (6/122) among children. No antibody to HIV was detected among Japanese or Bolivian populations. The results of this study show that: (1) there is a considerable number of HTLV-I carriers among Japanese immigrant populations in Bolivia, especially among immigrants from Kyushu, (2) there exist some HTLV-I carriers among Bolivian natives, raising the possibility of HTLV-I transmission by co-habitation with Japanese immigrants, (3) HIV is far from endemic in this district of Bolivia, at present.
The major structural difference between p60c-src and p60v-src resides in the carboxy-terminal region. We introduced substitution, replacement and deletion into the carboxy-terminal region of chicken p60c-src and examined the effects on its biochemical and biological properties in chicken embryo fibroblasts. The replacement of the carboxy-terminal region after amino acid position 515 of p60c-src with the corresponding region of p60v-src converted p60c-src to a transforming protein with elevated kinase activity. The substitution of Tyr527, which is a major tyrosine phosphorylation site of p60c-src, with phenylalanine resulted in an increase of kinase activity and in transforming ability. On the other hand, a deletion after position 515 abolished the kinase activity. These results revealed the structural features of the carboxy terminus of p60c-src that are required for the regulation of its intrinsic protein kinase activity.
The inductions of ornithine decarboxylase (ODC) and DNA synthesis in the pyloric mucosa of the stomach of male F344 rats after oral administrations of chemicals were studied. The glandular stomach carcinogens N-methyl-N'-nitro-N-nitrosoguanidine, N-ethyl-N'-nitro-N-nitrosoguanidine, N-propyl-N'-nitro-N-nitrosoguanidine, 4-nitroquinoline 1-oxide and N-nitroso-N-methylurethane induced up to 100-fold increase in ODC activity in the pyloric mucosa of the stomach; the activity was maximal 24hr after administration and returned to the control level after 48 to 72hr. These compounds also induced 14- to 30-fold increase in DNA synthesis in the pyloric mucosa of the stomach; synthesis was maximal 16 to 24hr after administration and returned to the control level after 144hr. The non-gastric carcinogens 2-acetylaminofluorene, dimethylnitrosamine and 3-amino-1-methyl-5H-pyrido[4, 3-b]indole (Trp-P-2) did not induce ODC or DNA synthesis in the pyloric mucosa of the stomach. Ethyl alcohol also did not induce ODC or DNA synthesis in the pyloric mucosa of the stomach. These results and previous findings that stomach-tumor protmoters such as NaCl, taurocholate, glyoxal, K2S2O5 and formaldehyde induced ODC and DNA synthesis in the pyloric mucosa of the stomach of F344 rats suggest that the inductions of ODC and DNA synthesis in the glandular stomach mucosa are markers of promotive activities of complete carcinogens and tumor promoters in the glandular stomach.
A murine monoclonal antibody (mAb), NCC-AS 13 (IgM, κ), was producedafter immunization with ascites from a gastric cancer patient. In a sandwich enzyme immunoassay, NCC-AS 13 reacted with the sera from 32% of 58 gastric cancer patients, 44% of 9 hepatocellular cancer patients and 33% of 6 colorectal cancer patients. Immunohistological analysis showed NCC-AS 13 to react with approximately 90% of 51 gastric carcinomas, 12 out of 12 colon carcinomas and 3 out of 4 lung carcinomas. The NCC-AS 13 defined antigen was determined to be a carbohydrate without terminal sialic acid on macromolecular glycoproteins. This mAb NCC-AS 13, detecting a novel antigen associated with gastrointestinal cancers, may have potential uses for tumor immunoscintigraphy and for the therapy of gastric cancer patients.
This report describes the production and characterization of monoclonal antibody specific for an antigenic determinant, designated Y1 antigen, present on Jurkat cells. Mo-Y1 specifically reacts with Jurkat cells, but not with other cell lines. Immunoprecipitation and subsequent immunochemical analysis demonstrate that Mo-Y1 defines an antigen with a molecular weight of 200, 000 and a pI value of 5.3 to 5.6. Rabbit antibody against affinity-purified Y1 antigen was prepared. A sequential immunoprecipitation study confirmed that Po-Y1 reacted with the same antigen molecule recognized by Mo-Y1. Interestingly, Mo-Y1 reacted only with Jurkat cells, whereas Po-Y1 reacted with various hematopoietic cells including T cells, B cells, macrophages, and granulocytes. Po-Y1 precipitated a 200, 000-dalton component from Jurkat cells and T cells. In contrast, Po-Y1 precipitated a 230, 000-dalton component from B cells. These data led us to examine the relationship between T200, leukocyte-common antigen and Y1-defined antigen. Sequential immunoprecipitation analysis clearly indicated that T200 antibody and Y1 antibody recognized the same antigen molecule. Peptide mapping of T200- and Mo-Y1-defined antigen digested with V8 protease demonstrated that there were two common major peptide chains, but one peptide chain was missing in Jurkat cells that was present in T200 glycoprotein of other cells. It is possible that minor molecular modification of T200 glycoprotein occurred in the process of oncogenesis of T cells and that the altered epitope of T200 glycoprotein was recognized by Mo-Y1. The Y1 antigen can be classified as a tumor-specific antigen.
The immunosuppressive activity of sera from adult T cell leukemia (ATL) patients and culture supernatants of ATL cells and ATL cell lines on B cell responses was examined in vitro. ATL sera and culture supernatants of ATL cells suppressed B cell proliferative and differentiative responses induced with B cell mitogens such as Staphylococcus aureus Cowan I and pokeweed mitogen. The suppressive effect was observed not only in the production of B cell growth factors (BCGF) and B cell differentiation factors (BCDF) by T cells, but also in the responsiveness of B cells to BCGF and BCDF. These results suggest that the immunosuppressive factors produced by ATL cells might act to suppress both the cellular immunity and the humoral immunity, and could have an important role in the induction of immunodeficient states in ATL patients.
The antitumor effect of recombinant human interferon-γ (rIFN-γ) and adriamycin (ADM), alone or in combination, against a human colon cancer cell line (RPMI 4788) was examined in vitro and in nude mice. In the in vitro study, antiproliferative activities of ADM were augmented additively or synergistically by combination with rIFN-γ in a dose-dependent manner. Growth of RPMI 4788 cells (2×106/mouse) transplanted subcutaneously into CD-1 nu/nu nude mice (day 0) was not inhibited significantly by 28 daily injections from day 10 of rIFN-γ alone, but the antitumor effect of ADM was augmented synergistically by the simultaneous injection of rIFN-γ. In an experimental model of pulmonary metastasis, in which RPMI 4788 cells (2×106/mouse) were inoculated intravenously into BALB/c nu/nu nude mice (day 0), 10 or 21 daily injections from day 2 of rIFN-γ alone had significant inhibitory effects against pulmonary metastasis in a dose-dependent manner. Furthermore, the inhibitory effect of ADM was augmented synergistically by daily injections of rIFN-γ.
Streptococcal acid glycoprotein (SAGP) was purified from the cultured cells of Streptococcus pyogenes Su, and its in vitro and in vivo antitumor activities were investigated in comparison with those of OK-432, a cell preparation of S. pyogenes Su which is used clinically as a potent antitumor agent. SAGP inhibited the growth of several tumor cell lines in vitro at less than 0.1μg/ml, while it did not affect the growth of the other tumor and normal cell lines even at 10μg/ml. This selective cytotoxicity is a unique characteristic of SAGP. OK-432 did not show cytotoxicity in vitro. SAGP also showed a considerable life-span-prolonging effect on mice bearing Meth A tumor and inhibited the growth of sarcoma 180 tumor implanted im. The comparison of antitumor activities between SAGP and OK-432 definitely suggested a difference in the mechanisms of their actions, even though they were derived from the same bacterial strain.
We have examined the expression of P-glycoprotein in clinical leukemic cell samples by using a monoclonal antibody (MRK16) against P-glycoprotein. We found that leukemia cells isolated from 3 out of 6 patients with blast crisis of chronic myelogenous leukemia were reactive to MRK16. These 3 cell lines expressed high levels of mdr1 mRNA, which codes for P-glycoprotein. The present result indicates that the clinically refractory state of the tumor may be predicted in part by determining P-glycoprotein expression using the monoclonal antibody against P-glycoprotein, and the mdr1 probe.
Female C3H/HeN mice were irradiated in the thorax at a dose ranging from 10 to 25 Gy with or without ACNU (nimustine hydrochloride) treatment in order to determine whether the chemotherapeutic agent would lead to an enhancement of radiation-induced lung damage. ACNU given intravenously at 15mg/kg immediately prior to irradiation reduced the mortality of mice irradiated with a low dose; mortality with either radiation alone or radiation plus ACNU was 4/10 (40%) or 0/10 (0%) at 13.1Gy, and 9/10 (90%) or 6/10 (60%) at 15Gy, respectively. The presence of ACNU during thoracic irradiation also prolonged the survival time of mice approximately 2-fold over that of animals given radiation alone. Histological examination of mice sacrificed 80 days after treatments revealed that the combination of drug and irradiation produced no radiation pneumonitis, which was predominant in mice given radiation alone. It is unexpectedly concluded that ACNU may have a protective effect against radiation-induced lung injury.