Transcription of the c-myc gene in chick embryo fibroblast cells was activated 50-to 100-fold by Rous sarcoma virus (RSV) infection. More than 30-fold activation of c-myc gene transcription was also observed in RSV-transformed rat cells as compared with the control cells. The increased expression of c-myc gene in these cells was not due to gene amplification or gene rearrangement. This striking increase in expression of c-myc gene may be relevant to neoplastic transformation of RSV-infected cells.

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A study of acetaminophen (AAP) for possible carcinogenicity was conducted by administering the test chemical in pelleted diets to F344/DuCrj rats of each sex. Groups of 50 rats were administered AAP at one of two doses, either 0.45 or 0.9% for males and 0.65 or 1.3% for females. The rats were treated for 104 weeks, and then observed for 26 weeks. Control groups of 50 rats were fed basal diet throughout the study. Mean intakes of AAP by low- and high-dose rats were 195.4 and 402.1 in the males, and 335.7 and 688.0mg/kg/day in the females, respectively. The survival rates at week 104 of each group were 86 to 90% in the males and 80 to 82% in the females. No pathologic or statistical evidence of induction of tumors by AAP was found. It is concluded that, under the conditions of this study, acetaminophen is not carcinogenic to F344/DuCrj rats of either sex.

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Rabbits were successfully infected with human T-cell leukemia virus type I (HTLV-I) and produced antibodies to adult T-cell leukemia-associated antigens (ATLA) on intravenous inoculation of the HTLV-producing human cord T-cell line MT-2, or autologous cell lines established by cocultivation with MT-2 cells. Lymphocytes taken from the rabbits between 4 and 14 days after the inoculation of MT-2 cells, but not lymphocytes obtained in earlier or later periods, could be immortalized in vitro and expressed ATLA and type C virus particles. However, lymphocytes harvested during an early culture period (5 to 8 days) were found to be negative for ATLA. The transformed cells had the karyotype of a normal male rabbit. Two rabbits inoculated with the autologous HTLV-producing cell lines did not allow their growth in vivo, but some peripheral blood lymphocytes could be immortalized in vitro. One of these transformed cell lines was examined for the integration of HTLV-I provirus genome. The transformed cells were found to contain the provirus genome and also to be monoclonal with respect to the integration site of the provirus genome, unlike the inoculated cells.

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Human ferritins purified from normal liver (LF) and from hepatocellular carcinoma (HF) showed different biochemical and immunological characteristics. Subunit preparations from the isoferritins showed differences in isoelectric focusing patterns, although both HF and LF were found to be composed of H and L subunits with apparently the same molecular weights. It is postulated that heterogeneities between the two isoferritins are not merely due to different proportions of H and L subunits, but also result from the existence of distinct species of the subunits bearing different surface electric charges.

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The radiosensitivity of a recurrent tumor following local radiotherapy was investigated in order to determine whether or not the cell(s) surviving radiotherapy are radioresistant. A tumor which recurred in a C3Hf/HeMsNrs male mouse 200 days after local irradiation of a transplanted syngeneic fibrosarcoma was examined. The recurrent tumor showed the same biological properties, such as karyotype, histological features, and ability to produce colony stimulation factor, as the original tumor. On the other hand, the tumor control dose and the D₀ value of the recurrent tumor were much smaller than those of the original tumor. Moreover, the recurrent tumor grew more slowly than the original tumor. It was concluded that initial radiotherapy might have changed the intrinsic radiosensitivity of the original tumor cells.

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Bile acids have been implicated in carcinogenesis of the large bowel, and since epidemiological, clinical and histopathological studies suggest a link between adenomatous polyps and cancer of the large bowel, fecal bile acid profiles were studied in 33 patients with adenomatous polyps of the large bowel and these data were analyzed with particular reference to the distribution, multiplicity, size and degree of dysplasia of the polyps. The more polyps and the greater the severity of dysplasia, the higher was the excretion of total bile acids (mean μmol/day: single vs multiple polyps, 344.8 vs 369.1; mild vs moderate vs severe dysplasia, 347.5 vs 370.0 vs 399.3). However, in patients with larger polyps, total fecal bile acid excretion tended to be lower (mean μmol/day: large vs small polyps, 267.7 vs 389.5). These differences were not statistically significant. When fecal bile acid profiles were analyzed with respect to the extent of bacterial metabolism determined from the degree of dehydroxylation and oxidoreduction, there was a large variation with no consistency in relation to the factors studied among the polyp patients. Deconjugation of bile acids in feces was almost complete without difference among the patients. These results seem to indicate that the significance of bile acid in the development of adenomatous polyps in Japanese subjects is likely to be small.

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Family history of cancer was examined for 9, 131 cancer patients who were reported to the Aichi Cancer Registry in 1979-1981, and were over 20 years old at diagnosis.The rate of patients whose parents and/or siblings had cancer of any site was 24.5%.The rate was 9.2% for father, 8.4% for mother, 6.0% for brother (s), and 5.2% forsister (s). A significant site concordance between study patient and family memberwith cancer was observed for cancer of the breast, colon and rectum, and stomach.The rate of family history of breast cancer for breast cancer patients was 3.3 timeshigher than the corresponding rate for other cancer patients (3.1% vs 0.9%). Similarly, the ratio was 2.2 in colon and rectum cancer (4.2% vs 1.9%), and 1.6 in stomach cancer(16.5% vs 10.1%). An increased risk of cancer was observed when both brother andsister had cancer. This may suggest an important role of environmental exposure at an early age, as well as genetic factors, in the development of cancer. The age distributioncurve of the colon and rectum cancer patients who had a family history of the same cancer was found to be bimodal with the larger peak in the 40s and the smaller peak in the 70s. This may suggest a differential contribution of genetic and environmental factors to the development of colon and rectum cancer.

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The cytotoxic agent purothionin purified from barley was covalently conjugated to the anti-human high-molecular-weight melanoma-associated antigen (HMW-MAA) monoclonal antibody (MoAb) 225.28S by utilizing water-soluble carbodiimide. Injection of the conjugate (0.1mg/injection) significantly increased the life span of nude mice injected with ascitic-form human melanoma cells (Colo 38), and caused 40% inhibition on day 25 of the growth of solid-form human melanoma cells in nude mice. The effect is specific and is markedly influenced by the site of growth of tumors and by the schedule of administration of the conjugate.

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The metabolism of 6-mercaptopurine (6-MP) in L-1210 mouse leukemia cells and human chronic myelocytic leukemia cells (CML cells) was examined. The acid-soluble fractions obtained from cells incubated with [8-¹⁴C]6-MP were chromatographed on a Dowex-1 formate resin column using a formic acid linear gradient elution system. Chromatography of the extract of L-1210 cells revealed four principal radioactive peaks. The fraction containing the third peak was hydrolyzed by snake venom 5'-nucleotidase (Crotalus adamanteus). Cellulose thin layer chromatography revealed that the radioactive peak of the hydrolysate corresponded to 6-thioguanosine. The results showed that 6-MP was converted to 6-thioinosinic acid (6-TIMP) and 6-thioguanylic acid (6-TGMP) in L-1210 cells. In order to elucidate the pathway of 6-MP conversion to 6-TGMP, we examined the interaction of [8-¹⁴C]6-TIMP and purified IMP dehydrogenase. It was found by DEAE-cellulose thin layer chromatography that the IMP dehydrogenase converted 6-TIMP to 6-thioxanthylic acid (6-TXMP). Dowex-1 chromatography of the acid-soluble extract of human CML cells incubated with [8-¹⁴C]-6-MP also revealed a radioactive peak corresponding to 6-TGMP. These results suggest that 6-MP is metabolized to 6-TGMP by serial conversion to 6-TIMP and 6-TXMP through the de novo GMP synthetic pathway in L-1210 cells and human CML cells.

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Continuous observation of living malignant cells (L1210) in a specially devised glass observation chamber with an inverted microscope made it possible to classify various cellular morphological features induced by antitumor agents into the following four stages: 1) an initial stage consisting of cytoplasmic granulation and coloring, 2) an intermediate stage of shrinkage of nuclei, increases of vacuoles and cytoplasmic budding, 3) a determinate stage of cell ballooning and 4) the terminal stage (cell ghost). Both the initial and intermediate stages are characterized by cellular changes that appear at an early phase and remain opportunistic in terms of viability. Emergence of these cellular changes is largely dependent on the specific mode of action of antitumor agents. In contrast, definite irreversibility in the changes found in both the terminal and determinate stages was confirmed by continuous observation until the cells showed lytic or ghost features, using a video-recording system. A plot of the number of cells counted in both the determinate and terminal stages versus the time-dose schedule is designated as the “time-dose-response” plot, and this proved useful for estimating the characteristics of the antitumor agents tested and the actions of new antitumor agents on malignant cells (predictive activity assay graph).

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Proflamin is a new biological response-modifying antitumor agent. It was isolated from the culture mycelium of Flammulina velutipes (Curt. ex Fr.) Sing. by means of ion exchange column chromatography and molecular sieving. It is a weakly acidic glycoprotein containing more than 90% protein and less than 10% carbohydrate, and its molecular weight is 13, 000±4, 000. The antitumor effect of proflamin was studied with murine tumors. It was markedly effective against the syngeneic tumors, B-16 melanoma (B-16) and adenocarcinoma 755 (Ca-755). At a dose of 10mg/kg po, the increases in median survival time of mice with B-16 and Ca-755 were 86 and 84%, respectively. Proflamin exhibited no cytocidal effect against the cultured cell lines in vitro. Oral administration of proflamin produced no lethal or any other apparent adverse effect in mice.

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The effects of improvements of clinical diagnosis and treatment of gastric cancer on the decline in gastric cancer mortality rate in Niigata Prefecture were evaluated. Analysis of mortality statistics since 1950 and registries of surgical cases with gastric cancer in the 10 years from 1972 provided the following conclusions. (1) The age-adjusted gastric cancer mortality rate (the demography of Japan in 1965 was used for the standard population) began to decline in 1968, and the mean mortality rates were 60.5per 100, 000 population in 1958-1967 and 38.6 in 1981, showing 21.9 decrease in 14 years in Niigata Prefecture. (2) Surgical cases increased from 1, 258 to 1, 870, and those of early gastric cancer in particular showed a rapid increase from 133 to 421 in 10 years (1972-1981). (3) The age-adjusted early gastric cancer rate in surgical patients increased from 4.6per 100, 000 population to 11.5 within 10 years. Since the 5-year survival rate of patients with early gastric cancer is more than 90%, 30.1 % of the decrease in the mortality rate should be attributed to patients with early gastric cancer who are surviving. (4) Improved diagnostic and therapeutic techniques for advanced gastric cancer might account for 16.0% of the decline in the mortality rate. (5) Overall, 46.1 % of the decline in the mortality rate can be ascribed to improved diagnostic and therapeutic techniques, and the remaining 53.9% to a decreased incidence of gastric cancer.

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