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Three new rat cell lines (designated as BP13, BP30 and BP36B), derived from rat basophilic-type renal cell carcinomas induced with N-ethyl-N-hydroxyethylnitrosamine, were established and characterized. Passaged up to 100 times in vitro for 3 years, each cell line forms epithelial monolayers with cell cycles for BP13, BP30 and BP36B of 29, 21 and 17 h, respectively. Positive glucose-6-phosphate dehydrogenase (G6PD) and gamma-glutamyltransferase (gamma-GT) activity in their cytoplasm, but negative succinate dehydrogenase (SD) and slightly positive carbonic anhydrase type II (CA) localization indicates an origin from proximal tubules. Ultrastructural examination showed the presence of variable numbers of mitochondria and many microvilli and intracellular junctions on the plasma membrane. BP13 and BP30 were found to be tetraploid and BP36B diploid. BP13 has one marker chromosome 15p+, and BP36B an isochromosome of 1q. Anchorage-independent growth and tumorigenicity in immunosuppressed nude mice of BP13 and BP36B, but not BP30, proved their neoplastic nature. These three cell lines should provide useful tools for studying the biological characteristics of renal cell tumors.

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PURPOSE: von Hippel-Lindau (VHL) gene mutations are detected in noninherited, sporadic human renal cell carcinomas (RCs) at a high frequency. We recently identified a germline mutation in the rat homologue of the human tuberous sclerosis (TSC2) predisposing RC gene in the Eker rat model, and in this study we searched for mutations of the Tsc2 gene in chemically induced non-Eker rat RCs. MATERIALS AND METHODS: Chemically [N-ethyl-N-hydroxyethylnitrosamine (EHEN)]-induced non-Eker rat RC lines (designated as BP13 and BP36B) were subjected to PCR-single strand conformation polymorphism (PCR-SSCP) analysis using specific primers covering entire exons of Tsc2 gene (41 coding exons and one non-coding exon). We simultaneously searched for mutations of Vhl gene, a rat homologue of von Hippel-Lindau disease gene (VHL) as well as Tsc2 gene. RESULTS: BP36B showed an abnormal mobility shift from the normal tissue of the same rat in exon 35 on analysis by PCR-SSCP. This mutation was confirmed by direct sequencing and found to be a T-to-C transition at the second position of codon 1470, resulting in an amino acid change from leucine to proline (missense mutation). CONCLUSIONS: This is the first demonstration of Tsc2 gene somatic mutation in non-Eker rat RCs. Our present findings call attention to further investigation of the role of Tsc2 gene mutations in rat renal carcinogenesis and possible Tsc2 gene mutations in human RCs, especially of the non-clear cell type, which are not related to the VHL gene.

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5-Phenethyl-2'-deoxyuridine (PEUdR) augmented 5-fluoro-2'-deoxyuridine (FUdR) cytotoxicity up to 100-fold in several human gastric cancer cell lines. PEUdR also potentiated 5-fluorouracil (5-FU) cytotoxicity about 5-fold. In contrast, PEUdR reversed 5-fluorouridine (FUR) cytotoxicity in all cell lines studied. PEUdR was not cytotoxic up to 200 microM. PEUdR inhibited the incorporation of [3H]thymidine and [14C]uridine into acid-insoluble fractions, and also inhibited uptake of [3H]thymidine into KATO III cells. Thus, PEUdR inhibits pyrimidine nucleoside transport and salvage enzymes, which potentiates the cytotoxicity of FUdR and reverses the effect of FUR in human gastric cancer cells. These results may contribute to more effective cancer chemotherapy with FUdR and 5-FU.

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Neplanocin A is a cyclopentenyl analog of adenosine which has been isolated from the culture filtrate of Ampullariella reqularis. Antitumor activity of twenty three derivatives of neplanocin A was examined against L1210, sarcoma 180 and L5178Y. Neplanocin A showed a marked inhibition of growth of L1210 in vivo. Other derivatives which had a 2' or 3'-substituted cyclopentene group showed weak cytotoxicity against L5178Y cells in vitro. Neplanocin A inhibited the biosynthesis of ribonucleic acid (RNA) and protein, while 6-chloroneplanocin A, a new active derivative, showed a specific inhibition of only RNA synthesis. The two hydroxy groups in the cyclopentene moiety with a ribose type structure are important for marked antitumor activity.

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The radiation response of spontaneously induced autochthonous mammary tumors was studies in SHN mice, a strain developed at the National Cancer Center. Tumors were mostly adenocarcinomas and grew with an average volume- doubling time of 3.0 days. When tumors reached a size of 8 approximately 10 mm in diameter, they were given a single, local irradiation with 6 MVp X-rays generated by a medical linear accelerator. With radiation doses lower than 2 krad, the tumours regrew after a temporary interruption. Surviving fractions of tumor cells in situ were estimated from the tumor cells in situ were estimated from the tumor regrowth times, yielding a survival curve with D0=480 rad for n=2. With 6.5 krad, tumor regression was very rapid: the volume-halving time was 1.7 days, and temporary tumor control was achieved. This rapid radiation response was not necessarily correlated with the radiosensitivity of tumor cells and is thought to be related to the structure of the mammary tumor mass. A disadvantage of this mouse strain was its high multiple tumor incidence which interfered with the observation of tumor control for adequate periods after irradiation.

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The antitumor activity of 1-hexylcarbamoyl-5-fluorouracil (HCFU) in various schedules of long-term oral administration was examined in spontaneous mammary adenocarcinoma of SHN mice, an autochthonous tumor system. In the control group, the average time to local recurrence and average longevity after surgical intervention were 21 and 48 days, respectively. Oral administration of HCFU at 200 approximately 300 mg/kg/day, 3 times a week for 5 consecutive days every 2 or 3 weeks was markedly effective against the adenocarcinoma. The optimal schedule was 20 administrations of HCFU at 300 mg/kg/day, 3 times a week. The average time to local recurrence after the operation was increased to 200% and average postoperative survival was also prolonged to 150%. Growth of the tumors was slower and lung metastases at autopsy were found to be suppressed by HCFU. The effect of HCFU in delaying local recurrence and prolonging longevity was slightly affected by the schedule of administration.

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The antitumor activity of the cell-wall skeleton (CWS) of Propionibacterium acnes C7 was examined by using transplantable tumors in syngeneic mice and in guinea pigs, and autochthonous tumors in mice. P. acnes-CWS was shown to suppress the growth of fibrosarcomas, EL4 leukemia, and MH134 hepatoma in syngeneic mice, and to regress the established tumors of a fibrosarcoma (MC104) in C57BL/6J mice, and a hepatoma (line-10) in strain-2 guinea pigs. The oil-attached P. acnes-CWS mixed with fructose mycolate was effective for suppression of the autograft of fibrosarcoma in mice. The repeated intralesional injections of suspension of P. acnes-CWS in phosphate-buffered saline was effective for prolongation of survival period of mice bearing 3-methylcholanthrene-induced fibrosarcoma. The test results on the cell fractions of P. acnes indicated that the CWS, but not the cytoplasmic or glucan fraction, of P. acnes had anti-tumor activity. The activation of peritoneal macrophages of mice was observed when P. acnes-CWS, but not the cytoplasmic fraction, was injected intraperitoneally 4 days before. The relationship between the cytolytic activity of peritoneal macrophages and antitumor activities of P. acnes-CWS was also discussed.

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Antitumor activities of the cell-wall skeleton of Nocardia rubra and related bacterial fractions in autochthonous tumor-host system were tested on autografts of spontaneous mammary adenocarcinoma in SHN mice and of 3-methylcholanthrene-induced fibrosarcoma in ICR/JCL mice. The oil-attached cell-wall skeleton of N. rubra was the most effective in suppressing the autografts of the mammary adenocarcinoma but less of the fibrosarcoma, when the autografts were mixed with oil-attached preparation and implanted subcutaneously in the original host, while peptidoglycolipid of Mycobacterium tuberculosis Aoyama B was the most suppressive on the autografts of the fibrosarcoma but not on the mammary tumor autografts. The cell-wall skeleton of Mycobacterium bovis BCG slightly suppressed the autografts of the fibrosarcoma. Presensitization of tumor-bearing mice with the cell-wall skeleton of N. rubra resulted in a more marked suppression on autografts of both tumors than without the presensitization, but local destruction of these tumor autografts did not induce recognizable systemic immunity to the respective tumors. Intralesional injection of cell-wall skeleton of N. rubra showed prolongation of survival days of mice with fibrosarcoma.

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The growth of spontaneous mammary tumors and of tumors transplanted into the animals with different hormonal conditions was compared between SHN and SLN strains of female mice established from the same basal stock of Swiss albino as a high and a low mammary tumor strains, respectively. There were little differences between strains in the growth of spontaneous mammary tumors of multiparous mice which appeared first. The growth of transplanted mammary tumors was not affected by the hormonal conditions of the hosts in either strains. However, the tumors became palpable one week after transplantation in SHN, which was 2 weeks earlier than in SLN. These findings indicate that the selection of animals for mammary tumorigenesis is effective on the time and frequency of malignant transformation of mammary cells and on the ""take'' of transplanted tumor cells, but not on the growth potentiality of already established tumors. They further suggest autonomy in the growth of mammary tumors in both strains of mice.

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Two mouse strains (SHN and SLN) with high and low incidences, respectively, of mammary tumors were established from the same basal stock of Swiss albino mice that were unrelated in origin to other mouse strains with mammary tumors. In the breeders, mammary tumor incidence and average age of the mice when they developed mammary tumors were 97.2 % and 6.6 months for SHN, and 5.57% and 10.1 months for SLN, respectively...

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Cytotoxic cytidine analog, cyclocytidine, and antitumor immunopotentiator, lentinan, offered an opportunity of testing the effect of combined modality of cytocidal agent and immunopotentiator on spontaneous mammary tumors of mice. Lentinan did not improve the therapeutic effect of cyclocytidine; it only prevented the early toxic death of mice due to cyclocytidine in one strain of mice but not in the other strain.

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Adjuvant and antitumor activities of CWS prepared from cells of mycobacteria, nocardia, and corynebacteria were examined. Oil-attached CWS of M. bovis BCG (BCG-CWS) stimulated the generation of cell-mediated cytotoxic effector cells in mice. Tumor growth was suppressed in mice inoculated intradermally with a mixture of oil-attached CWS and living tumor cells. Systemic and specific tumor immunity was demonstrated in mice in which tumor growth was suppressed. Tumor growth was also suppressed by oil-attached CWS of BCG or N. rubra in autochthonous autografts of spontaneous mammary adenocarcinoma and methylcholanthrene-induced fibrosarcoma in mice. The intravenous injection of oil-attached BCG-CWS prevents the appearance of lung cancer in rabbits by the instillation of chemical carcinogens. It was also shown that treatment with oil-attached BCG-CWS was able to elevate the immunologically depressed state of tumor-bearing mice to a normal level, as determined by a cell-mediated cytotoxicity assay that empolyed chromium release as the standard. Preliminary results suggest that oil-attached BCG-CWS is useful as an immunotherapeutic agent for both lung cancer and for malignant melanoma, leukemia, Hodgkin's disease, and other neoplastic diseases and that this agent operates without any significant complications.

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Cell-wall skeleton of Nocardia rubra and of Mycobacterium bovis BCG in the oil-attached form, when injected mixes with autografts of spontaneous mammary adenocarcinoma or of methylcholanthrene-induced sarcoma of mice, suppresses the growth of tumor autografts to a demonstrate extent. The BCG whole cell wall showed no effect. The local destruction of tumor autografts did not induce recognizable systemic immunity to the respective tumors. These findings are commended upon from immunological and chemical points of view.

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