The c-myc oncogene was found to be rearranged in a human cell line of giant cell carcinoma of the lung (C-Lu65) and in a human primary giant cell carcinoma of the lung (LuC38C). The rearrangements in C-Lu65 and LuC38C were in regions about 7.5kb and 6kb, respectively, upstream from the transcription initiation site. No rearrangement of the c-myc gene was observed in a non-cancerous portion (LuC38N) of the lung of the patient who carried LuC38C. These results suggest that rearrangement of the c-myc gene may play some role in tumorigenesis of giant cell carcinoma of the lung.

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The low risk of colon cancer among the Japanese suggests a high intake of dietary fiber. Composite diets for 1959, 1970, and 1979 were prepared using food consumption data from the National Nutrition Survey in Japan and analyzed for non-starch polysaccharides (NSP) at the Dunn Clinical Nutrition Centre in Cambridge. The results showed that average intake of NSP by Japanese in the above years did not exceed 13g per day, which is as low as the corresponding intake by the Scandinavians and the British, whose risk of colon cancer is known to be high.

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A single oral instillation of 1.5g/kg body weight of sodium taurocholate resulted in a rapid, transient stimulation of ornithine decarboxylase activity in rat glandular stomach mucosa, reaching a peak (10 times the control value) 4 to 6hr after sodium taurocholate treatment and returning to the control level within 48hr. The degree of stimulation was dose-dependent. Sodium taurodeoxycholate and sodium taurochenodeoxycholate stimulated the enzyme activity similarly.

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The cumulative incidence rate throughout the life span was analyzed for 4, 865 Hodgkin's disease cases, in comparison with 16, 015 malignant lymphomas (ML), 1, 694 acute lymphocytic leukemias (ALL), 3, 967 acute myeloid leukemias (AML), 2, 109 chronic myeloid leukemias (CML), and 4, 752 chronic lymphoid leukemias (CLL) in US white reported in the SEER program during 1973-1981. A log-linear increase was observed in ML, AML, CML, and CLL throughout the life-span, but only in childhood in ALL. Hodgkin's disease showed a steep increase until age 20-24, and then the increase became much more gradual. The cumulative incidence rates for males and females were parallel for ML and leukemias, but diverged for Hodgkin's disease (the rate for females had a lower slope than that for males after age 20-24). This difference was mainly caused by a lower frequency in females of mixed cellularity and lymphocyte predominance subtypes. The incidence curve of Hodgkin's disease was consistent with the two-stage model of carcinogenesis; it is likely that the proliferation of progenitor cells peaks at a young age and that the death rate of so-called intermediate cells is a primary influence during the subclinical stage. The cytogenesis of Hodgkin's disease and the histologic variation with special reference to the T-zone histiocytes suggest that a strong host defense mechanism against neoplastic change is involved, rather than different etiologic influences.

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The effect of fumaric acid was examined on DNA synthesis in hepatocytes or hepatoma cells from rats treated with toxic agents. Male Donryu rats were injected with mitomycin C or aflatoxin B₁, singly or in combination with fumaric acid. After a specified period, hepatocytes were isolated from the liver by the collagenase perfusion method and placed in culture, and their activities for DNA synthesis were measured. The iv injection of rats with mitomycin C (0.5mg/kg) reduced the semiconservative DNA synthesis of the hepatocytes, but simultaneous dosing of fumaric acid (40mg/kg) enhanced the recovery of the DNA synthesis. The DNA synthesis of hepatoma cells, a 3'-methyl-4-(dimethylamino)azobenzene-induced transplantable cell line growing in the abdominal ascites of rats, was also reduced by the iv injection of mitomycin C but, in contrast to that of the hepatocytes, was little influenced by the simultaneous dosing of fumaric acid. The ip injection of fumaric acid also reduced the toxicity of aflatoxin B₁ (0.25mg/kg, ip), preventing the reduction of DNA synthesis as well as the occurrence of nuclear degenerative changes in the aflatoxin B₁-exposed hepatocytes.

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Detailed chromosome studies on cultured skin fibroblasts from patients with familial polyposis coli (FPC) and Peutz-Jeghers' syndrome (PJS) showed an increased incidence of chromosome aberrations at early passage levels, as compared with the age-comparable controls. The occurrence of certain clones of karyotypically abnormal cells was recognized in both groups of patients. There was no clear evidence for the emergence of such clones in the controls within the range of the number of cells observed. Our observations may suggest that the increased chromosome instability in the FPC and PJS patients is due to a genetic predisposition rather than an age-related expression of a normal phenomenon. The present studies, however, have not revealed any specific break or exchange point, although several sites were involved in three or more rearrangements.

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Interleukin 1 (IL1) has been suggested to have antitumor activity but there is no clear-cut evidence of an in vivo antitumor effect of pure IL1. In this work, the antitumor effect of purified recombinant human IL1 alpha (rHu-IL1α) was assessed on murine tumors transplanted intradermally in syngeneic female mice. rHu-IL1α inhibited the growth of Meth A sarcoma in BALB/c mice, B16 melanoma in C57BL/6 mice and colon 26 adenocarcinoma in CDF1 mice, as well as the spontaneous pulmonary metastasis of Lewis lung carcinoma in BDF1 mice, at intratumoral (itu), intramuscular (im), and/or intravenous (iv) doses ranging from 1 to 30μg/mouse. The antitumor effect of rHu-IL1α was generally dose- and route-dependent, being highest by the itu route, followed by the im and iv routes in that order. Palpable 7-day-old Meth A sarcoma was completely regressed in some mice given rHu-IL1α itu once at doses of 10-30μg/mouse (cured ratio; 71-100%), once a day for 3 days at doses of 3-30μg/mouse (57-86%) or once a day for 7 days at doses of 1-10μg/mouse (14-100%). Palpable 7-day-old B16 melanoma was also regressed completely in some mice given seven itu doses of 10-30μg/mouse (14-86%). One-day-old Meth A sarcoma was more sensitive to rHu-IL1α than 7-day-old Meth A sarcoma. There was no macroscopic sign of inflammation at the site of injection of rHu-IL1α. These results show that rHu-IL1α has antitumor activity in vivo and is worthy of further study as a potential antitumor agent.

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The antitumor effect of murine recombinant interferon (β) [Mu-rIFN(β)] was examined on artificial metastasis of B-16 melanoma in C57BL/6 mice. The numbers of pulmonary nodules were significantly decreased to 16.7±4.7 (P<0.01), 9.5±4.2 (P< 0.01), 7.1±5.6 (P<0.01) in mice given 20, 000 units of Mu-rIFN(β) intraperitoneally (ip) 24, 6, and 3hr before intravenous tumor inoculation, respectively, compared with the control group of mice (57.1±1.4), if B-16 melanoma cells (5×10⁵) were intravenously injected 28 days before the experiment. In mice given 20, 000 units of Mu-rIFN(β) ip 24, 6, and 3hr before the experiment, the natural killer (NK) activities of spleen cells against YAC-1 cells were elevated to 45.5±6.1%, 53.7±3.4%, 43.2±6.5%, respectively, compared with NK activities in control mice (20.3±3.1%). Similarly, NK activities against B-16 melanoma cells were also elevated in mice given Mu-rIFN(β). Pretreatment with anti-asialo GM1 antibody and carrageenan reduced the inhibitory effect of Mu-rIFN(β) on the pulmonary metastasis. In vitro colony inhibition of more than 50% was not observed even if B-16 melanoma cells were incubated with 100, 000 units/ml of Mu-rIFN(β). From these results, it can be concluded that the inhibition of pulmonary metastasis by Mu-rIFN(β) is mediated via host defense mechanisms and that NK cells and macrophages are both important for the inhibition.

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Forty-five patients with advanced non-small cell lung cancer were randomly allocated to receive vindesine (3mg/m² every week) plus either high-dose cisplatin (120mg/m² every 4 weeks) or low-dose cisplatin (80mg/m² every 3 weeks). All patients were previously untreated. The response rate for the high-dose regimen of cisplatin was 39% (9/23) and that for the low-dose regimen of cisplatin was 33% (7/21); the difference was not statistically significant. Only one patient treated with high-dose cisplatin achieved complete response, lasting 6.5 months. The median duration of response was 5.6 months (range, 2.7-7.7) in the high-dose cisplatin group and 6.8 months (range, 1.9-8.9) in the low-dose cisplatin group. The median survival times for the 23 patients treated with the high-dose regimen of cisplatin and for the 21 patients treated with the low-dose regimen of cisplatin were 9.0 and 10.8 months, respectively. Significantly more azotemia occurred in the high-dose cisplatin group than in the low-dose cisplatin group (P<0.05). Combination chemotherapy with cisplatin and vindesine showed significant antitumor activity in patients with non-small cell lung cancer. However, the high-dose regimen of cisplatin did not result in a significantly better response rate or survival advantage, and was associated with greater toxicity.

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A 53-year-old man complained of anorexia and abdominal distention of one month's duration. The chest X-ray demonstrated a mass in the left lung with hilar and mediastinal adenopathy and a lytic lesion in the right fourth rib. A transbronchoscopic biopsy of the mass revealed oat cell carcinoma (WHO classification). The endoscopic evaluation also revealed a gastric lesion (IIc type). Biopsy of this lesion indicated signet ring cell gastric cancer. An abdominal CT scan demonstrated multiple liver metastases. Based on these findings, the patient was diagnosed as having synchronous lung and gastric primaries, with liver and bone metastasis from lung cancer. Carboplatin (CBDCA) was administered by intravenous drip infusion of 450mg/m². After a second treatment with CBDCA about 3 weeks later, the patient achieved a partial response at the primary site of lung cancer as well as at the liver and bone metastases. In addition, repeat endoscopy of the stomach demonstrated a complete regression. A biopsy specimen taken by gastroscopy was negative for cancer cells. Subsequent chemotherapy for small cell lung cancer was administered with cyclophosphamide, adriamycin, and vincristine, and to date there is no evidence of recurrence. Further studies on CBDCA treatment of small cell lung cancer and gastric cancer are needed to establish the efficacy of this drug against these two histologically different cancers.

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Eleven thyroid carcinoma patients of 15 years old and under are reported. They represent only 1.3% of our personal series of 861 thyroid carcinoma cases. One case died from undifferentiated carcinoma of the thyroid. However, the other 10 cases of papillary or follicular carcinoma are all alive, in spite of the apparently advanced stage of the disease at the time of operation in most of the cases. From our experience and analysis of 127 cases of childhood thyroid cancer reported in the Japanese literature, it is suggested that childhood thyroid cancer constitutes an extreme case of thyroid cancer occurring in the adolescent and young adult periods, and that rather conservative surgical treatment, avoiding total laryngectomy, and preserving the recurrent laryngeal nerve and the parathyroid glands as far as possible, usually suffices for treatment. In these Japanese cases, radiation did not appear to have been an important causative factor of childhood thyroid cancer.

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A fraction extracted from BCG and designated MY-1, which was composed of 70.0% DNA and 28.0% RNA, was previously reported to possess strong antitumor activities against various syngeneic mouse and guinea pig tumors. An intraperitoneal injection of MY-1 (100μg) 1 day before rendered mouse peritoneal cells cytotoxic to YAC-1 cells. The effector cells were nonadherent to plastic dishes, and the activity was destroyed by treatment with anti-asialo GM1 antiserum plus complement or carrageenan in vitro, but not with carbonyl-iron or anti-Thy 1.2, suggesting that the cells are natural killer (NK) cells. In vivo augmentation of NK activity was dependent on MY-1 dose, and reached the peak 1 day after MY-1 injection. Since NK activity in lipopolysaccharide (LPS)-nonresponder mice could be augmented by MY-1, the possibility that LPS contaminated the MY-1-augmented NK was excluded. MY-1 digested preliminarily with DNase lost its NK-inducing activity, suggesting that the DNA entity of MY-1 was essential for the activity. When mice were pretreated with anti-asialo GM1 or carrageenan, MY-1 could not render the peritoneal cells cytotoxic. Antitumor activities of MY-1 were also abolished if the animals were pretreated with anti-asialo GM1 antiserum or carrageenan, suggesting that the activities can be ascribed mainly to activated NK cells.

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We investigated the various conditions necessary for potentiating the immunogenicity of viable Friend virus (FV)-infected rat fibrosarcoma KMT-17 cells. The immunogenicity was most potent among cells passaged through three generations of FV-tolerant rats; a single subcutaneous immunization induced an increase in the transplantation resistance (LTD₅₀) of 10, 000 or more. It was also found that intradermal immunization of the tumor cells induced stable and potent resistance to the transplantation of non-xenogenized tumor cells soon after immunization, and that irradiated non-xenogenized tumor cells were effective in supplying booster immunization. Active immunotherapy against KMT-17 cells pre-transplanted subcutaneously was carried out on the basis of the above findings with the results that the active anti-tumor immunization alone caused a complete regression in 30% of the tumor-burdened rats. These findings indicate the possibility of achieving active immunotherapy with xenogenized tumor cells.

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The present study deals with the role of cells sensitive to anti-asialo GM1 antibody treatment in T cell-mediated tumor cell radication in vivo. Rabbit anti-asialo GM1 antiserum was injected into C3H/He mice. This treatment not only resulted in almost complete abrogation of natural killer (NK) cell activity but also produced a potent inhibiting effect on the generation of activated macrophage activity induced by inoculating Propionibacterium acnes (P. acnes). Such an immunodepressed state lasted for 20 days or more after 5 consecutive injections of anti-asialo GM1 antiserum. These antiasialo GM1 antibody-treated C3H/He mice were used as recipients in Winn assays, in which the neutralizing activity of spleen cells immunized to syngeneic X5563 tumor cells was assessed. The results demonstrated that anti-X5563 immune spleen cells depleted of asialo GM1-positive cells by the in vitro treatment with anti-asialo GM1 antibody plus complement exhibited potent anti-X5563 tumor-neutralizing activity in antibodyuntreated normal recipient mice. In contrast, the X5563-immune spleen cells depleted of asialo GM1⁺ cells failed to produce tumor protection in asialo GM1 antiseurm-treated recipient mice. When T cell-deprived B cell mice were used as recipients in Winn assays, X5563 immune spleen cells depleted of asialo GM1⁺ cells exhibited or failed to exhibit tumor-neutralizing activity in asialo GM1 antiserum-untreated or-treated recipient B cell mice, respectively. These results indicate that the implementation of T cell-mediated in vivo protective immunity requires the participation of anti-asialo GM1 antibody-sensitive cells, but not necessarily the host's T cells.

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Tumor-associated transplantation antigen (TATA) was solubilized with n-butanol from rat gliosarcoma cells (T-9). Under the conditions used for the solubilization of TATA, the viability of T-9 cells was maintained above 85%, suggesting that the contamination of TATA with cytoplasmic protein is minimal. Normal Fischer rats were treated with 500μg of n-butanol extract and inoculated with 2×10⁶ viable T-9 cells. At 8 weeks after the inoculation of viable tumor cells, the tumor diameter was significantly smaller than that in control untreated rats. Rats treated with 770μg of n-butanol extract from T-9 cells were inoculated with 1×10⁷ syngeneic FTL-13 thymic lymphoma cells or T-9 cells. The rats rejected the T-9 cells, whereas the FTL-13 cells grew gradually until the host died, indicating that the n-butanol extract from T-9 cells contained T-9 cell-specific TATA. The n-butanol extract was characterized by chromatographic separation on a TSK gel G3000SW gel filtration column and a Mono Q anion exchange column with the fast protein liquid chromatography system (FPLC). The TATA of T-9 cells was found to have a molecular weight of approximately 40, 000-70, 000 and was eluted at 0.6-0.9M NaCl from the Mono Q column. The cellular mechanisms responsible for the rejection of T-9 cells in the rats treated with the n-butanol extract were also examined. Adoptive transfer and in vitro experiments demonstrated that helper T cells for the generation of cytotoxic T lymphocytes were generated in the rats treated with n-butanol extract.

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