The promoting effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the occurrence of neurogenic microtumors in SD-JCL rats initiated transplacentally with N-ethyl-N-nitrosourea (ENU) was investigated. The treatment with TPA induced earlier occurrence of microtumors than as compared with the initiation alone. Thus, TPA has tumor-promoting activity on the formation of neurogenic microtumors in rats prenatally exposed to ENU.

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Based on incidence and survival data from the Osaka Cancer Registry, the numbers of cancer survivors were estimated by site in this study. The method used for estimation of survivors from all sites of cancer in the previous study was simplified further by not subdividing the data according to age-group. The observation period was the 25 years from 1960 to 1984. The number of incident cancers at all sites that occurred during the 25 years was estimated as 4, 776, 100. The leading sites of incidence during this 25-year period were the stomach (1, 612, 000), lung (427, 100), and liver (329, 100) for both sexes. The number of total cancer survivors on January 1, 1985 was estimated as 1, 009, 100. Among males, stomach cancer survivors accounted for 45% (180, 100) of all survivors. The next most common sites were the rectum (7%, 27, 000) and colon (6%, 25, 600). Among females, the leading sites were the uterus (26%, 157, 600), breast (22%, 132, 100) and stomach (18%, 106, 800). Most of the cancer survivors living at not more than 5 years after diagnosis were assumed to be receiving some kind of cancer medical care and were therefore regarded as an approximation of what is generally called “cancer prevalence.” The number in this category for all sites was estimated as 417, 900. The sites showing the largest numbers of these short-term survivors were again the stomach, followed by the rectum and colon among males, and the breast, uterus, and stomach among females. The reliability and utility of the results are discussed. The results are compared with other recently reported registry data from other countries and with other estimated data in Japan.

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The mortality data on stomach cancer in Japan during 1955 to 1980 were analyzed by the use of an age-period-cohort model. Although the model could not give a unique solution of age, period, and cohort parameters, several sets of estimates of the parameters clarified particular features of each effect. Within a plausible range, the features were as follows. The period parameter underwent linear change from 1965 to 1980 for males and from 1970 to 1980 for females. The cohort parameters decreased birth cohort by birth cohort, at least among those who were born after 1891. The curve of the age parameter in females showed a shoulder around age 40 and a subsequent upward slope to age 80, while that in males was unimodal. The curve in females was compatible with the idea that there might be two different main entities in stomach cancer. The model also gave estimates of future trends in stomach cancer mortality under the assumption that there would be no additional change in period effect other than that expected from the recent quinquennia. The number of deaths from stomach cancer in males would be rather stable until 2000, and that in females would decline slightly. The age-adjusted and crude mortality rates would continue to decrease at least until 2000.

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The incidence of bronchial squamous metaplasia in Japanese lungs was investigated in order to clarify the significance of this lesion for the development of lung cancer of various histological subtypes. The bronchi of 104 and 32 lungs resected, respectively, for primary or metastatic tumors were step-sectioned and examined histologically. The incidence of squamous metaplasia was particularly high (83% of cases, 8-11% of sections) in male lungs bearing primary squamous or small cell carcinoma whereas it was low (43% of cases, 3% of sections) in lungs of both sexes with adenocarcinoma, the latter figures being about the same as those for lungs with secondary metastatic tumors. Although the overall incidence of lung squamous metaplasia in Japanese is much lower than in the U.S., the present data demonstrate a high level in association with squamous or small cell carcinoma, directly comparable to that of Americans. However, atypical metaplasia, or dysplasia, was encountered much less frequently than in the U.S. A topographical study of 7 minute or small squamous cell carcinomas revealed 3 to have adjacent and 2 to have nearby areas of squamous metaplasia. However, 2 cases were found to be completely free of squamous metaplastic lesion. Thus, squamous metaplasia may be associated with the development of squamous cell carcinoma but would appear not to be an obligatory step in the development of this neoplasm.

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The initiating, promoting and carcinogenic activities of three naphthofurans, 2-nitro-7-methoxynaphto[2, 1-b]furan (A), 2-nitronaphtho[2, 1-b]furan (C) and 7-methoxynaphtho[2, 1-b]-furan (E), were determined in a long-term assay using CD1 mice, by means of a two-step skin painting regimen. Compound A was a strong initiator and a weak carcinogen, and compound C was a strong promotor and a moderate carcinogen, whereas compound E did not have any effect. The NO₂ group at the 2 position on the molecule was concluded to be responsible for the carcinogenic activity of the former two naphthofurans. The addition of a CH₃O group at position 7 enhanced the initiating ability while it diminished the promoting and carcinogenic potentials. These findings indicate that the initiating activity is closely linked to the mutagenic potential previously detected in in vitro and in vivo mammalian cell systems, while the promoting and carcinogenic activities are related to the effects detected in mouse short-term skin tests.

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The effect of the duodenal ulceration induced by cysteamine hydrochloride on the development of gastroduodenal tumors initiated by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was studied in F344 rats of both sexes. Cysteamine (200mg/kg body wt.) was administered by gastric intubation at various times, before, during or after a 16 week period of MNNG (100mg/liter in drinking water) treatment. In the preliminary experiment, while the ulcers induced were confined to the proximal duodenum, the pyloric region of the stomach also showed slight erosion. Five of 25 male rats given cysteamine 2 weeks before the start of MNNG treatment developed adenocarcinoma in the duodenum as compared to 1 case in the MNNG alone group. In addition, animals of both sexes which received cysteamine during MNNG treatment yielded significantly increased incidences of adenocarcinoma in the pyloric area of the stomach. In line with earlier reports, the present findings suggest that mucosal damage and subsequent regeneration or proliferation of mucosa are important co-factors for MNNG-induced gastroduodenal carcinogenesis in rats.

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(-)-Indolactam-V, which has the partial structure of teleocidins A and B, and has tumor-promoting activity, is a good model for use in studies on the relation between structure and tumor-promoting activity, whereas (+)-indolactam-V has no tumor-promoting activity. In this work, five racemic indolactams differing only in their alkyl group at C-12 of (-)-indolactam-V were synthesized and tested for biological and biochemical activities related to tumor promotion. The activities tested were inductions of ornithine decarboxylase in mouse skin and human promyelocytic leukemia (HL-60) cell adhesion, inhibition of specific [³H]12-O-tetradecanoyl-phorbol-13-acetate binding to a mouse particulate fraction and activation of protein kinase C in vitro. The results showed that (±)-indolactam-L and (±)-indolactam-F had almost the same activities as (±)-indolactam-V, suggesting that (-)-indolactam-L and (-)-indolactam-F are new tumor promoters with as high potency as (-)-indolactam-V. (±)-Indolactam-t-L, which has a highly lipophilic group at C-12 of (-)-indolactam-V, showed the highest activities in the above tests. (-)-Indolactam-t-L might have stronger tumor-promoting activity than (-)-indolactam-V. Furthermore, the results with (-)-indolactam-t-L indicated the possibility of designing new tumor promoters with stronger activity than teleocidin.

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The effect of 3'-azido-3'-deoxythymidine (AZT) on replication of human immunodeficiency virus (HIV) in various hematopoietic cell lines was investigated. The concentration of AZT required to block HIV replication varied depending on the cell line used. U-937 cells required as little as 0.01μMAZT to block HIV replication, a concentration almost 100 times lower than that required for MT-4 or MOLT-4 cells. However, 467 and TALL-1 cells required concentrations of AZT higher than 5μM. It was clear that AZT was ineffective once the viral gene was integrated into chromosomal DNA; removal of AZT from culture fluids at that stage allowed the full expression of HIV. The effect of the potent immunostimulator lentinan was also examined, and it was shown that lentinan enhanced the effect of AZT.

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We studied chromosome 22 breakpoints in 24 Philadelphia (Ph¹)-positive leukemias. Nineteen of 21 patients with chronic myelogenous leukemia (CML) possessed a chromosomal break within the 5.8 kilobase (kb) breakpoint cluster region (bcr). Furthermore, in one of three cases of acute lymphocytic leukemia (ALL), we found a chromosomal rearrangement in the bcr locus. No chromosomal rearrangements were found in two cases of CML and two cases of ALL using several restriction enzymes. The bcr rearrangement is highly specific for CML. Further analyses will be necessary to determine whether some cases without bcr rearrangement have another specific locus of rearrangement. Two of three cases of CML with blastic crisis had rearrangement of the immunoglobulin gene and T-cell receptor gene. One CML patient with blastic crisis, who achieved complete remission but relapsed thereafter, was found to have the same immunoglobulin gene rearrangement in the blastic crisis and relapse phases, suggesting that the same clone was involved in both crisis and relapse.

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The effects of anemia-inducing substance (AIS), found in the plasma of tumor-bearing subjects, on red blood cells (RBC) and cellular immunity were examined. The results obtained may be summarized as follows: 1) The osmotic resistance and the deformability of RBC were decreased in patients with terminal cancer. 2) Normal human RBC were made less deformable and their membrane was made fragile by treatment with cachectic plasma from those patients, and these changes in physical properties were irreversible. 3) Energy metabolism in RBC was affected by AIS, that is, ATP concentration and pyruvate kinase activity in RBC were lowered and transmembrane glucose influx was suppressed. 4) AIS was removed from cachectic plasma by repeated adsorption with normal RBC, and the inhibitory effect on cellular immunity was lessened as AIS was removed. 5) AIS was detected in cachectic RBC membrance, monocytes, and tumor tissue by indirect immunofluorescence assay using rabbit anti-AIS antibody prepared by us. These observations suggest strongly that tumor-derived AIS appears in the blood of patients with terminal cancer, shows cytotoxicity to RBC and immunologically competent cells, and plays a role in the pathogenesis of cancer cachexy.

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A sandwich enzyme immunoassay was established to measure an adenocarcinoma-associated antigen (antigen YH206) detected by monoclonal antibody YH206. Levels of antigen YH206 exceeding the cut-off value (25U/ml) were found in the following percentages of 163 patients with various cancers: stomach cancer 37.2%, colon cancer 14.8%, pancreas cancer 43.3%, common bile duct cancer 28.6%. In contrast, only one out of 33 (3.0%) healthy donors and 7 of 104 (6.7%) patients with benign diseases had slightly elevated levels of the antigen. As regards the relationship between antigen YH206 levels and clinical stages, abnormally high levels of the antigen were found in the following percentages of 29 patients with stomach cancer: stage I 16.7%, II 0%, III 42.9% and IV 54.5%. Serial monitoring of antigen YH206 in two patients with cancer revealed that the level of the antigen increased as the disease progressed. It was also found that perchloric acid treatment of serum might be useful to decrease any false-positive reactions.

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The specificity of antibody to NeuGcα2-3Galβ1-4Glc-cer (GM3(NeuGc)) was carefully reexamined by the method of enzyme-immunostaining on a thinlayer plate. The affinity-purified antibody was found to react with NeuGcα2-8NeuGcα2-3Galβ1-4Glc-cer (GD3(NeuGc-NeuGc)) and NeuGcα2-8NeuAcα2-3Galβ1-4Glc-cer (GD3(NeuGc-NeuAc)), but not with NeuAcα2-8NeuGcα2-3Galβl-4Glc-cer (GD3(NeuAc-NeuGc)) or NeuAcα2-8NeuAcα2-3Galβ1-4GIc-cer (GD3(NeuAc-NeuAc)). From this result together with the previous results, it could be concluded that the antibody recognizes the outer portion of molecular species of sialic acids in the gangliosides. By using this antibody, the expression of Hanganutziu-Deicher (HD) gangliosides could be demonstrated in human malignant melanoma. The molecular species were different among individuals examined. Among HD-antigenic gangliosides, GM3(NeuGc) was commonly found in melanoma tissues. One of the patients examined expressed GD3(NeuGc-NeuGc) and GD 3(NeuGc-NeuAc), which may be characteristic gangliosides in human melanomas, since these gangliosides could not be detected in human colon cancer or human fetal tissues.

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By means of TLC immunostaining with anti-asialo GM1 antiserum and conventional structural analyses including exoglycosidase treatment, permethylation and negative ion FABMS, asialo GM1 was found to be widely distributed in rat ascites hepatomas, AH130, AH109A, AH44, AH272, AH41C, AH60C, AH414, AH7974, AH66, AH66αF, AH66F and AH13, and Yoshida sarcoma cells. However, reactivity of asialo GM1, when measured by flow cytometry and complement-mediated cytotoxicity assay with anti-asialo GM1 antiserum, was only observed on AH13 and AH66F, and did not necessarily correspond to the concentration of asialo GM1 on the cells, indicating a cryptic or unreactive nature of glycosphingolipids with respect to their antibodies. On the other hand, although rats injected with 10⁷ cells of AH66F died within 7 days, treatment of the rats with anti-asialo GM1 antiserum was found to be effective for their cure or for prolonging their survival, indicating an in situ cytotoxic effect of antiserum. For the in situ cytotoxicity, the timing and period of injection and the dose of antiserum were found to be important.

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