Regional blood flow and capillary permeability in the experimental brain tumors and their surrounding brain tissue of rats were measured with quantitative 14C-antipyrine and 14C-alpha-aminoisobutyric acid (AIB) autoradiographic method. The pharmacokinetic implications with respect to drug delivery to tumor tissue and the effect of ionizing irradiation were discussed in these physiological measurement. A suspension of 1 X 10(4) rat glioma cells (E239 RG 12) was stereotactically implanted into the right basal ganglia of CD-Fisher rats, and spherical brain tumors developed 10-17 days after implantation with a diameter of 1--5 mm. Autoradiographic investigations were performed for rats with small tumors (1--2 mm in diameter) and large tumors (4--5 mm in diameter). The uniform blood flow (91.7 +/- 13.1 ml/100 g/min: mean +/- S.E.) was observed in small tumors with the patchy low flow area (56.7 +/- 12.5 ml/100 g/min) surrounding the tumor. In large tumors, the blood flow was markedly decreased in the central part of the tumor (28.3 +/- 2.4 ml/100 g/min) with a ring shaped high flow area in the peripheral part (59.3 +/- 5.9 ml/100 mg/min). The blood flow in the brain adjacent to the tumor (30.5 +/- 2.5 ml/100 g/min) was lower than that in the peripheral part of the tumor. The uptake of 14C-AIB was quite similar to that of 14C-antipyrine suggesting the smaller permeability in the central part of the tumor. Neuropathological studies did not reveal necrotic foci, but viable cells in these areas.(ABSTRACT TRUNCATED AT 250 WORDS)

The pancreatic duct cell adenocarcinoma induced by di-isopropanol nitrosamine in Syrian golden hamsters could be easily and repeatedly into the subcutaneous tissues or the pancreas of the homologous animals. We examined the anti-tumor effects of the administration of FT-207 and the coadministration of FT-207 and uracil on the pancreatic cancer transplanted into the subcutaneous tissues and the pancreas. The inhibitory effect on the tumor growth observed in the group treated with FT-207 and uracil was more striking than that in the group treated with only FT-207. Such enhanced anti-tumor effect observed in the coadministration group seemed to be due to the increased 5-FU concentration in the tumor tissues. Some gastrointestinal hormones (cholecystokinin, caerulein, secretin and tetragastrin) injected intraperitoneally promoted the growth of subcutaneously transplanted tumor. These gastrointestinal hormones except tetragastrin also increased the weight of the pancreas. In an analysis of RNA and DNA contents and RNA/DNA ratio in tumor tissues, the promotion of the tumor growth seemed to stem from hyperplasia and/or hypertrophy of the cancer cells. Therefore, it is suggested that some gastrointestinal hormones have trophic actions on the pancreatic duct cell adenocarcinoma as well as normal pancreas.

The experiments were performed in order to reveal the role of prostaglandins in the implantation process, using indomethacin, a inhibitor of prostaglandin synthesis. Indomethacin was administered to mice on various days of pregnancy, and then the number of implantation sites and the uterine weight per the number of implantation sites were determined on day 10 of pregnancy. Furthermore [3H]uridine incorporation of blastocysts incubated in the medium containing indomethacin with/without prostaglandin F2 alpha was evaluated in vitro. The results were as follows. Indomethacin reduced the number of implantation sites in the uterus and the uterine weight per the number of implantation sites (embryonal growth). Indomethacin inhibited the [3H]uridine incorporation of blastocysts, but prostaglandin F2 alpha counteracted the effect of indomethacin. These results suggested that prostaglandins play a role in inducing implantation and embryonal growth, and that blastocysts might synthesize prostaglandins.

Using our new in vitro antitumor sensitivity assay, the basis of which depends on predictive analysis of morphological findings of L1210 leukemia cells under the influence of antitumor agents, 5 kinds of nitrosoureas including MCNU were comparatively tested for antitumor activity. A cell killing effect became apparent very soon under BCNU and CCNU, rather late under Methyl-CCNU and MCNU, and intermediately under ACNU. Various cellular biological effects were apparently induced in L1210 cells by MCNU and its mechanism of action seemed to be broader than that of any other members of the nitrosoureas.

After a long and energetic world-wide search for antibiotics from actinomycetes, the chances of finding new classes of biologically active compounds from these organisms seem to have drastically diminished. In this paper, sophisticated procedures for finding new potentialities of antibiotic-producing actinomycetes and isolating a novel class of antitumor antibiotics, the saframycins, are described. These antibiotics are satellite antibiotics which are co-produced in minute quantities with streptothricin by a strain of Streptomyces lavendulae. Saframycins, cyano-containing saframycin A in particular, are promising antitumor antibiotics because of their low toxicity to immunologically competent cells and organs, especially the bone marrow. Significant amplification of the yield of saframycin A was attained by the quite unexpected observation that the addition of cyanide to the culture broth significantly increased its production. Subsequent isolation of the saframycin A precursor, decyanosaframycin A or saframycin S, enabled us to prepare two kinds of labeled saframycin A which were critical for the elucidation of the unique molecular action mechanism of the antibiotic. On the basis of studies on saframycin biosynthesis, a method of preparing new saframycin derivatives using resting cells of the producing strain has been developed, and new saframycins with amino functional groups on their N-pyruvoyl side chain were obtained. Their HCl salts are readily soluble in water and are expected to exhibit pharmacodynamic properties different from those of other saframycins.

Forty-one non-selected patients with malignant brain tumors have been treated since 1976 with chemoimmunotherapy using ACNU and PSK postoperatively. Eleven (27%) of these cases have survived usefully over five years, including 6 cases (30%) out of 20 with glioblastoma (astrocytoma III, IV approximately Kernohan). This long-term survival response for glioblastoma was considered to be better than any previous figures in the literature. Among these 6 cases, one child of 11 years old with brain stem tumor was found to be so significantly improved by chemoimmunotherapy that no surgery was needed. In another patient with astrocytoma III of the bilateral thalamus, the tumor was seen to be diminished so completely on CT examination after administration of ACNU(100 mg x 4), that no surgery was needed except for external decompression and was needed except for external decompression and biopsy. In three other cases local (intracavitary) chemotherapy was performed successfully. Local concentration of ACNU in these latter cases 24 h after its insertion was verified as being markedly higher than that in peripheral blood and brain tissues after intravascular administration. In an immunological study of these brain tumors, parameters such as lymphocytes and T cells in peripheral blood and Ig(G.A.M) in serum were examined. The results showed that these parameters were almost at normal levels in long-term survival patients (Group I), low in short-term survivals patients (Group II died) and normal in all control cases (Group III benign brain tumors, traumatic disorders etc.). Combined administration of PSK was considered to be very effective for the improvement of these parameters.