Dietary administration of 5% sodium citrate to male F344 rats clearly promoted the induction of preneoplastic and neoplastic lesions of the bladder initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine. Enhancement of tumorigenesis by sodium citrate was associated with changes in a number of urinary parameters: apparent elevation of pH; increase of sodium ion concentration; increase of crystalline MgNH₄PO₄. These results show that sodium citrate promotes bladder carcinogenesis.

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Using C3H/10T-1/2 mouse fibroblasts, we tested whether polyprenoic acid (E-5166) inhibits radiogenic and chemically induced transformation in vitro. Our results show that E-5166 markedly inhibits transformation by X rays and benzo[a]pyrene in a doserelated manner. Maximum inhibition was observed when cells were pretreated with E-5166 prior to carcinogen exposure, and lesser inhibition when E-5166 treatment followed carcinogen exposure. These results indicate that E-5166 can serve as a radio-protective and chemopreventive agent with anticarcinogenic potential.

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It was found that cell clones cl-2, cl-2^r, cl-3, cl-4 and cl-6 of a spontaneous rat mammary tumor, c-SST-2, exhibit different degrees of metastatic ability: cl-2, cl-3, cl-6 were highly metastatic, while cl-2^r and cl-4 were weakly metastatic. The expression of several oncogenes in these clones was examined. The amounts of myc mRNA in the clones were nearly the same. Expression of N-ras mRNA was higher in cl-2^r and cl-4 than in cl-2, cl-3 and cl-6. On the other hand, the amounts of fos mRNA in the weakly metastatic clones were markedly lower than those in the highly metastatic clones. These results suggest that fos oncogene plays a role in the high metastatic ability of c-SST-2.

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Peripheral blood lymphocytes from 2 normal individuals seronegative for human T-cell leukemia virus type I (HTLV-I) were co-cultured with HTLV-I-producing MT-2 cells that had been heated at 56° for 30min or exposed to 10, 000rad of X-irradiation. HTLV-I-induced lymphocyte transformation was consistently achieved by co-culture with irradiated MT-2 cells but not by coculture with heated MT-2 cells. The heat treatment was found to be lethal to both MT-2 cells and the virus. These findings are discussed in terms of their potential clinical application for preventing the transmission of HTLV-I.

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We attempted to isolate acquired immune deficiency syndrome (AIDS) virus from a Japanese hemophiliac with AIDS-related complex (ARC). After cocultivation of leukocytes from his peripheral blood with those of a healthy adult, reverse transcriptase activity and AIDS viral antigens were detected by immunofluorescence and radio-immunoprecipitation methods, respectively. Moreover, an electron microscopic study revealed the presence of viral particles consistent with AIDS virus. These retroviruses were further propagated. We designated this first Japanese isolate of AIDS virus as YU-1.

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A survey of carriers of antibodies to HTLV-specific antigens was made in 11 islands among 60 Okinawan islands to examine the regional variation in the prevalence of HTLV carriers. The overall seropositive rate was 21% among 7, 545 adults aged 40 years or more. The incidence of virus carriers was low in only one of the 11 islands (1-6%), while it was 14-31% in the other 10 islands.

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The immunoglobulin κ light-chain gene was rearranged in a Burkitt lymphoma cell line with the t(2;8) (pll;q24) translocation, KOBK101, showing recombination between the variable and the joining regions on one allele and an aberrant substitution of the region upstream of the J5 segment with an unknown sequence on another allele. Because DNA segments homologous to the consensus sequences of joining and switching regions of immunoglobulin genes were detected in the unknown sequence, we speculate that the system for either V-J or switching recombination in immunoglobulin genes may be involved in forming this unusual rearrangement.

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In an attempt to look further at the problem of heterogeneity, we have studied the immunoglobulin (Ig) gene organization in leukemic cells from 20 children with acute lymphoblastic leukemia (common ALL). Nineteen cases were divided into two subgroups: 12 cases with rearrangement of the Ig heavy (H) chain genes and 7 cases with rearrangement of both the Ig H and light (L) chain genes. No Ig gene rearrangement was found in one case. These findings indicate that there is more heterogeneity among patients with common ALL than has previously been believed.

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Glycyrrhetic acid suppressed tumor promoter-induced effects in vitro, such as stimulation of ³²Pi-incorporation into phospholipids of cultured cells and down-regulation of the epidermal growth factor receptor. Glycyrrhetic acid inhibited the promoting activity of both 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin on skin tumor formation in mice initiated with 7, 12-dimethylbenz[a]anthracene (DMBA). The percentage of tumor-bearing mice in the group treated with DMBA plus teleocidin was 88% at week 18, whereas that in the group treated with DMBA plus teleocidin and glycyrrhetic acid (10μmol/painting) was 6%. Similarly, the percentage of tumor-bearing mice of the group treated with DMBA plus TPA was 97% at week 20, whereas that of the group treated with DMBA plus TPA and glycyrrhetic acid was 40%. Therefore, glycyrrhetic acid was proved to inhibit the activity of two different tumor promoters, teleocidin and TPA, in mouse skin.

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The metabolic fate of N-nitrodibutylamine (NO₂DBA) and N-nitrobutylamine (NO₂BA) was investigated in the rat. Eight N-nitramines, including glucuronides, were isolated and identified from urine of rats given NO₂DBA. They were produced by ω, ω-1, ω-2 and α oxidations of the N-nitramine. The in vivo metabolic pattern of NO₂DBA was similar to that of N-nitrosodibutylamine, except that the monodealkylated metabolite NO₂BA was also isolated and characterized. When NO₂BA was administered to rats, no N-nitramine other than a small amount of unchanged NO₂BA was identified in the urine. Besides N-nitramines, N-acetyl-S-(butyl, 3-oxobutyl and 3-hydroxybutyl)-L-cysteines were isolated and identified (as their methyl esters) from the urine of rats given both NO₂DBA and NO₂BA. The relative ratio of these three L-cysteine derivatives obtained from NO₂DBA was quite similar to that from NO₂BA, indicating that NO₂DBA produces in vivo a chemical species with butylating ability through NO₂BA.

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A 576 base-pair DNA encoding human c-Ha-ras protein (p21) with a valine codon at position 12 has been synthesized by ligation of chemically synthesized oligodeoxy-ribonucleotides. The duplex was inserted into a plasmid with the E. coli tryptophan promoter and was expressed in E. coli efficiently.

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By DEAE-cellulose chromatography, the 30, 000g supernatants of human neuroblastoma (n=7), ganglioneuroma (n=5), sympathetic ganglia (n=3), and Schwannoma (n=2) were found to contain three major peaks of adenosine 3', 5'-cyclic monophosphate (cAMP) phosphodiesterase (PDE) activity, which were termed peaks I, II, and III in the order of their elution from the column. Peak I isozyme was calmodulin-dependent, and had two different K_m values for cAMP (32 and 2.3μM) and a low K_m for guanosine 3', 5'-cyclic monophosphate (cGMP) (2.9μM). Peak II isozyme had a high K_m for both cAMP, 76μM, and cGMP, 32μM, and peak III isozyme was a cAMP-PDE with K_m of 1.8μM. The peak II and III isozymes were calmodulin-independent. The activity ratio of peak I isozyme to peak III isozyme (I/III isozyme ratio) was significantly different (P<0.001) in neuroblastoma and in ganglioneuroma/sympathetic ganglia, i.e., 0.23±0.11 for neuroblastoma vs. 0.79±0.20 for ganglioneuroma and 0.51±0.08 for sympathetic ganglia. Schwannoma showed the highest value of 1.05 (P<0.05). These results suggest that the I/III isozyme ratio of cAMP-PDE could be a useful marker in studies on the differentiation of neural crest-derived tumors and Schwann cells.

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The effects of hot-water extract of pine cone (PCE) of Pinus parviflora Sieb. et Zucc. on the growth and differentiation of ML-1 cells, derived from a patient with human myeloblastic leukemia, were investigated. Growth of ML-1 cells was slightly inhibited at 3% (v/v) PCE, and a cytotoxic effect appeared at >10%. Growth inhibition was accompanied by conversion to morphologically macrophage-like cells with α-naphthyl acetate esterase activity. In contrast, PCE dose-dependently increased the Fc receptor and nitroblue tetrazolium (NBT)-reducing activity up to 3%; above 3% its effect declined. Most of the cytotoxic activity was extracted from PCE with ethanol, and separated from the insoluble pellet, which contained the differentiation-inducing activity. The differentiation-inducing activity was eluted near the void volume on Sephadex G-200 gel filtration, with a 260-fold increase in the specific activity.

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In order to elucidate further the mechanisms of central necrosis formation and drug delivery into tumor tissue, the interstitial fluid pressure in the normal subcutis and in rat ascites hepatoma AH109A and AH272 tumors was measured by means of a modified diffusion chamber technique. Using our apparatus for determining tissue pressures, we can obtain an exact zero reference-point and thus analyze daily changes in tumor interstitial fluid pressure. Tumor interstitial fluid pressure was found to be always positive and significantly higher than that in the normal subcutis, which was negative (P<0.001). The pressure increased with tumor growth. Highly significant correlations between the tumor size and the tumor interstitial fluid pressure were observed in both AH109A (r=0.87; P<0.001) and AH272 (r=0.86; P<0.001). The rate of increase in this pressure differed between AH109A and AH272 (P<0.001). It is concluded that the elevated interstitial fluid pressure in tumors could induce central necrosis and attenuate drug delivery to tumor tissue.

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Twenty-two cases out of a total of 683 patients (3.2%) with primary immunodeficiency diseases registered in the All-Japan Immunodeficiency Registry were reported to have developed malignant diseases. In the childhood patients with ataxia-telangiectasia the incidence of death due to malignancy was approximately 625 times higher than that of the normal Japanese childhood population. The incidence of lymphoproliferative disorders, such as malignant lymphoma, in Chediak-Higashi syndrome and the incidence of non-Hodgkin lymphoma and various carcinomas in ataxia-telangiectasia were both high, 37.5% and 13.7%, respectively. Only one case out of 45 with Wiskott-Aldrich syndrome was reported to have malignant lymphoma. The data obtained were compared with international statistics reported by the Immunodeficiency Cancer Registry.

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The effects of pure recombinant human interferonαA/D (IFNαA/D) on natural killer (NK) activity and the experimental lung metastasis of B16-F10 melanoma were studied. Treatment of C57BL/6 mice with IFNαA/D augmented splenic NK activity and also inhibited the experimental lung metastasis of B16-F10 melanoma in a dosedependent manner. The augmentation of NK activity and the inhibition of experimental lung metastasis by IFNαA/D were completely abolished in anti-asialo GM1-pretreated mice. These results suggested that the effector cells which inhibited melanoma metastasis in the present system were mainly NK cells, and that it was by activating NK cells that IFNαA/D had its effect. We next studied the timing of IFNαA/D administration for the most effective prevention of melanoma metastasis. The inhibitory effect of IFNαA/D was most pronounced when it was given 12hr before or at the same time as melanoma inoculation. This suggested that melanoma cells were susceptible to NK cells only for a short period of time after intravascular invasion.

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Little is known about the relative effectiveness and potency of a variety of treatments for malignancy-associated hypercalcemia, or how beneficial the reversal of hypercalcemia is to these patients. Therefore, 146 trials of treatment for hypercalcemia between 1980 and 1983 at the National Cancer Center Hospital, Tokyo, were evaluated retrospectively. Serum calcium levels exhibited the largest decrease in the mithramycin-treated group (decrease; 5.4±1.8mg/dl, mean±SD, n=22), followed by the groups given calcitonin plus glucocorticoids (3.1±2.3, n=11), glucocorticoids (2.3±2.3, n=18), calcitonin (1.8±1.6, n=51), hydration (1.3±2.5, n=27), and indomethacin (1.0±2.3, n=17). The effective rate was the highest with mithramycin (100%) and then with calcitonin plus glucocorticoids (73%) and with glucocorticoids (61%); it was less than 50% in the other modalities of treatment. In patients with pretreatment serum calcium levels of 14mg/dl or more, the survival rate improved significantly in those whose serum calcium levels decreased below 12mg/dl compared with those whose serum calcium remained above 12mg/dl (50% survival; 35 vs. 9 days, P<0.01). These data provide a good guideline and a rationale in choosing the modality of treatment. In addition, the data show that the gain in the survival time achieved by successful treatment of hypercalcemia is clinically significant, because it is long enough to conduct additional antitumor therapy.

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Experimental combined hormone therapy with tamoxifen, aminoglutethimide and medroxyprogesterone acetate was investigated using three hormone-dependent human breast carcinomas serially transplanted into nude mice. The antitumor effect of combined tamoxifen and aminoglutethimide was better than that of either tamoxifen or aminoglutethimide alone. Since aminoglutethimide significantly reduced the level of estrogen and the uterine weight in normal female mice, the antitumor effect of combined tamoxifen and aminoglutethimide was assumed to be a result of the low estrogen level produced by aminoglutethimide, favoring the competition of tamoxifen with estrogen receptors. There was no additive antitumor effect of the combination of tamoxifen and medroxyprogesterone acetate, although serum medroxy-progesterone acetate levels in nude mice were almost equivalent to those of humans. These results indicate that combination hormone therapy, especially with tamoxifen and aminoglutethimide, might be a promising method for clinical application.

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