A splice donor site of pX mRNA of human T-cell leukemia virus type I was elucidated by analyzing a cDNA clone of poly A⁺ RNA isolated from cat fibroblast cells infected with the virus. The donor site was located near the 5' end of the env gene. The putative N-terminal amino acid sequence of the pX protein was deduced to be Met-Ala-His---.

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The immunological cross-reactivity of human T-cell leukemia virus type I (HTLV-I)-related sera with lymphadenopathy virus (LAV) was investigated. The sera tested were obtained from 36 adult T-cell leukemia patients, 182 HTLV-I carriers, and 284 control individuals in Nagasaki. Two test methods were utilized: indirect immunofluorescence on LAV-producing cells and solid-phase radioimmunoassay with lysate of LAV. The results were exclusively negative for the presence of antibody activity against LAV, indicating the absence of cross-reaction and endemy in Nagasaki.

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Interferon(IFN)-α and -β strongly inhibited syncytia formation of human T-cell leukemia virus (HTLV). They also inhibited transmission of HTLV to normal human fibroblasts. These phenomena suggest a physiological role of IFNs in defense against HTLV infection.

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A modified nucleic acid base was isolated from liver DNA of rats treated with 1-nitropyrene. The structure of the modified nucleic acid base was identified as 1-(guanin-8-yl)-aminopyrene by comparison with an authentic sample.

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The causative agents of swimmer's itch were isolated from the marine blue-green alga, Lyngbya majuscula, which grows off the coast of the Okinawa islands, Japan. Nuclear magnetic resonance and mass spectral studies revealed that these agents were identical with aplysiatoxin and debromoaplysiatoxin, which were previously shown to be the causative agents of swimmer's itch in Hawaii. Aplysiatoxin and debromoaplysiatoxin were recently found to be potent tumor promoters in two-stage carcinogenesis in mouse skin. This is the first report that humans are directly affected by these potent environmental tumor promoters in Japan.

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The level of c-Ki-ras-2-specific mRNA was found to be markedly enhanced (10- to 20-fold) in a human epidermoid lung carcinoma transplanted into nude mice, compared with that in other lung carcinomas. Analysis of DNA revealed that c-Ki-ras-2 gene was amplified approximately 10-fold in this carcinoma, while c-Ha-ras, c-myc and c-sis were not amplified. Chromosome abnormalities were also observed in this carcinoma.

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The effect of catechol on the development of urinary bladder tumors in Fischer rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was studied. A solution of 0.05% catechol and 0.001% BBN was administered in the drinking water ad libitum for 78 weeks. The urinary bladders were then removed and examined microscopically. No statistically significant difference was observed between the experimental group receiving 0.001% BBN with 0.05% catechol and animals receiving 0.001% BBN alone with respect to the incidence of hyperplasia, papilloma, or carcinoma of the urinary bladder. Animals receiving 0.05% catechol alone in the drinking water had no macroscopic or microscopic lesions significantly different from those in control animals receiving tap water. Analyses of the urine of animals receiving catechol in their drinking water indicated that >99% of the catechol present was in the form of either glucuronide or sulfate conjugates. In a second bioassay, the potential cocarcinogenicity of catechol, administered together with BBN, was explored by direct instillation into the urinary bladder. The development of calculi and possible infections of the urinary tract within all groups of treated animals suggests that this bioassay technique for cocarcinogenicity is of questionable value. These data show that catechol at the dose and mode of administration employed in this study did not affect the epithelium of the urinary bladder or enhance the carcinogenic activity of BBN.

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The absorption characteristics of 3-amino-l-methyl-5H-pyrido[4, 3-b]indole (Trp-P-2), a mutagen-carcinogen present in tryptophan pyrolysate, in the gastrointestinal tract was investigated in Wistar male rats by an in situ loop technique. Trp-P-2, a weak base with a pK_a of 8.2, was poorly lipophilic below pH 5 and therefore the gastric absorption was negligible at pH 1.1 and 3.0. On the other hand, this compound was rapidly absorbed from the small intestine even at pH 4.0 and the absorption was even faster at higher pH where the unionized fraction increases. The absorption from the large intestine was also rapid. Although the intestine is one of the major metabolic organs for ingested materials, metabolism of Trp-P-2 by the scraped mucosa of the small intestine was slow in comparison with that in the liver. Formation of directacting mutagens (towards S. typhimurium TA98) associated with the metabolism was also much slower in the small-intestinal mucosa than in the liver. These results suggest that this mutagen is activated mainly after being incorporated into the liver, and are consistent with the liver-specific carcinogenicity of Trp-P-2 in rats.

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Potentially lethal damage repair or recovery (PLDR) after X-irradiation was examined in three experimental murine tumors, EMT6 sarcoma, SCCVII carcinoma and RIF1 sarcoma, by an in vivo-in vitro assay. All tumors were transplanted subcutaneously (sc) and, in the case of EMT6, also intradermally (id), in the thighs of syngeneic mice. Apparent PLDR was observed at high dose levels in the id and se EMT6 sarcomas and in the sc SCCVII carcinoma, but not in the se RIF1 sarcoma. In both id EMT6 and SCCVII tumors, PLDR appeared to be complete within 9 hr after X-irradiation. Dose-modifying factors due to PLDR evaluated at the surviving fraction of 0.01 were 1.34, 1.15, 1.24 and 0.97 for id EMT6, sc EMT6, SCCVII and RIF1 tumors, respectively. The amount of PLDR correlated inversely with the velocity of tumor growth in vivo, suggesting that slowly growing tumors might be proficient in PLDR. Although PLDR in id EMT6 and SCCVII tumors was evident in the dose range above 15Gy, the capacity to recover from PLD became smaller at lower doses; in SCCVII tumors, this phenomenon was negligible below 7.5Gy. PLDR did not seem to be a major factor influencing the radiocurability of these murine tumors, especially at low dose levels.

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The diurnal rhythms of the contents of serum corticosterone and liver glycogen and the activity of liver tyrosine aminotransferase gradually shifted forward in C3H/He mice bearing BFO osteosarcoma. The production of alkaline phosphatase by the tumor showed a circadian rhythm. The eating behavior of tumor-bearing mice seemed to be responsible for their change in circadian rhythm.

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The effects of DNA-crosslinking agents (mitomycin C and cisplatin), a DNA-intercalating agent (adriamycin) and monofunctional psoralen adducts (4-methyl-4', 5'-dihydropsoralen plus near-UV radiation or 8-methoxypsoralen plus narrow band 395nm light) on DNA replication and cell-cycle progression of cultured mouse mammary carcinoma cells were studied and compared at a dose of each agent sufficient to cause complete inhibition of cell growth. In cells treated with the DNA-crosslinking agents, inhibition of incorporation of [³H]thymidine occurred progressively upon incubation of the treated cells, and finally the cells were arrested at the G2 phase. However, although the mode of inhibition of DNA replication or cell-cycle traverse was the same as that of the crosslinking agents, adriamycin did not completely block cell progression at the G2 phase and some of the cells entered the G1 phase. In contrast to these agents, monofunctional psoralen adducts inhibited DNA replication immediately after treatment and no shift in the distribution of cells in the cell-cycle was observed during incubation. These results suggested different responses of the cells to different types of DNA damage.

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Clinicopathological features were examined in 150 hepatocellular carcinoma cases autopsied from 1977 to 1983 in the Philippines and were compared to those of cases reported in Japan. The characteristics of hepatocellular carcinoma in the Philippines were as follows. 1. The age of autopsied patients with hepatocellular carcinoma in the Philippines was approximately 10 years younger than in Japan. The Philippines cases included even 10- to 11-year-old patients. 2. The macroscopic type of hepatocellular carcinoma in the Philippines consisted predominantly of the massive type of Eggel's classification. On the other hand, an encapsulated tumor was found in only one case. 3. The histological characteristics of hepatocellular carcinoma in the Philippines were not especially well defined. Hyaline globules and fatty metamorphosis were found in 1 and 12, respectively, of 90 Philippine hepatocellular carcinoma cases. 4. The frequency of HBs antigen in hepatocellular carcinoma in the Philippines was 37%. This is almost equal to that in Japan.

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The accurate diagnosis of malignant tumor type is essential to enable the correct therapeutic regimen to be followed and to predict a patient's prognosis. However, the differential diagnosis of “small-round-cell” tumors, represented by neuroblastoma, rhabdomyosarcoma, lymphoma/leukemia and Ewing's sarcoma, can occasionally be difficult by conventional morphological and biochemical methods. If tumor membrane markers were available, these could provide rapid and accurate diagnostic aids. In the present work, a panel of 9 monoclonal antibodies raised against hematopoietic cells (BA-1, BA-2, J-5 and B7/21), brain cells (UJ-13A, UJ-127-11 and anti-Thy-1), and neuroblastoma cells (HSAN1.2 and PI153/3) was used to analyze the membrane phenotypes of 12 neuroblastoma, 4 rhabdomyosarcoma and 3 Ewing's sarcoma cell lines and cells of 3 fresh bone marrow tumors. BA-1, UJ-127-11 and PI153/3 antibodies may be useful for the differential diagnosis of neuroblastoma from rhabdomyosarcoma and Ewing's sarcoma.

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In an attempt to analyze the pathological processes which lead to hypercalcemia in patients with multiple bone metastases, 23 advanced breast cancer patients with multiple bone metastases, three hypercalcemic patients with other malignancies and seven early breast cancer patients without any distant metastasis were studied. Of the 23 patients with advanced breast cancer, nine showed serum calcium levels higher than 10mg/dl. In five of the nine hypercalcemic patients with advanced breast cancer, urinary cyclic AMP excretion was lower than 4nmol/100ml of glomerular filtrate (GF), indicating that the secretion of parathyroid hormone was suppressed. However, urinary cyclic AMP excretion was higher than 4nmol/100ml of GF in the other four hypercalcemic patients with advanced breast cancer and three hypercalcemic patients with other malignancies. In patients with higher urinary cyclic AMP excretion, fractional excretion of calcium (FE_Ca) showed a negative correlation (r=0.83, P<0.05) with urinary cyclic AMP. Parathyroid hormone immunoreactivity was not detected in any of six patients showing serum calcium levels higher than 11mg/dl. These results suggest that in about a half of hypercalcemic patients with advanced breast cancer and multiple bone metastasis, there is a factor which increases urinary cyclic AMP and enhances calcium reabsorption in the kidney, but which is different from parathyroid hormone. This factor may facilitate retention of calcium mobilized into the circulation by bone metastases, and lead to hypercalcemia.

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Squalene (SQ) was examined for ability to potentiate the cytotoxicity and antitumor activity of anticancer agents. The dose-response curves of cell survival of cultured HeLa or V79 cells in the presence of various anticancer agents [adriamycin (ADM), 5-fluorouracil (5-FU), bleomycin (BLM) and cis-dichlorodiamminoplatinum (CDDP)] showed that SQ potentiated the cytotoxicity of these anticancer agents. SQ may enhance the cytotoxic effect of ADM by interfering with the efflux of ADM from the cells. The antitumor activities of these anticancer agents combined with SQ were tested against sarcoma 180 (S180) ascites cells. Some combinations were found to show synergistic antitumor effects: ADM, BLM or CDDP with SQ was effective against S180, but only slight if any synergistic effect was observed with the combination of 5-FU and SQ. The antitumor activity of BLM was most strongly potentiated by SQ, among the tested agents.

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