The effect of NK-421(Bestatin) and Ge-132 (an organic germanium compound) on the ADCC and natural killing (NK) activities of the spleen cells of MH-134 tumor-bearing mice were studied. In the tumor-bearing mice, the ADCC activity was enhanced, and NK activity was reduced in accordance with the progress of the tumor. By oral administration of Bestatin at doses of 5, 10 and 50 mg/kg, ADCC activity was potentiated, and at a dose of 10 mg/kg, NK activity was significantly increased. Intraperitoneal administration of Ge-132 at 50 mg/kg potentiated the ADCC activity of tumor-bearing mice. A higher activity was observed in the plastic dish adherent fraction. Ge-132 also potentiated the reduced NK activity of tumor-bearing mice to higher level than normal mice. The elevated activities of ADCC and NK following Bestatin and Ge-132 administration were decreased with anti-Thy-1 antibody and complement; however, the percent reduction was lower compared to that of the control cancer animals. This result indicates that Bestatin and Ge-132 may act on non-T cells and augment ADCC and NK activities.

The sensitivity of leukemic progenitor cells (L-CFU) to cytosine arabinoside (Ara-C) and daunomycin (DM) in vitro was studied using PHA -LCM two step assay for L-CFU. Continuous exposure of leukemic and normal bone marrow cells to DM as well as Ara-C in vitro appeared to be more effective than pulse exposure because colony formation was suppressed by a dose dependent fashion. The relationship between in vitro sensitivity to DM and Ara-C and that of in vivo to chemotherapy was investigated in 17 untreated and 5 relapsed patients with acute nonlymphocytic leukemia. The sensitivity of L-CFU to the two chemotherapeutic agents varied from patient to patient. These studies indicated a clear-cut relationship between in vitro drug sensitivity and in vivo response to patients whose L-CFU were sensitive to both agents and entered complete remission, whereas patients whose L-CFU were insensitive to one or both drugs in vitro failed to enter remission. This assay system appears to be useful in predicting response of patients to chemotherapy and in selecting the most effective drugs for an individual patient use.

The combination effect of heat and anti-cancer drugs were studied by following the proliferation of cancer cells from a uterine cervix (OG cells). In animal experiment, tumor bearing mice were injected 5 microCi 14C-5FU, local hyperthermia was created in hot water baths of 37 degrees C, 43 degrees C and 45 degrees C for 30 minutes. At timed intervals, tissue was taken from the tumor and radioactivity was measured. The results were as follows: In vitro. The critical temperature for proliferation was between 40 degrees C and 41 degrees C with continuous heating. At 60 minutes of heating was between 45 degrees C and 46 degrees C. The simultaneous use of heat and anti-cancer drugs that inhibit cell proliferation was effective for Bleomycin, Cis-plantinum and Ifosfamide but not effective for Mitomycin and Adriamycin. In vivo. Immediately after the hyperthermia, the uptake of 14C-5FU within the tumor in the 37 degrees C group was (229 +/- 29) X 10dpm/g. The 43 degrees C group (1.47 times) and the 45 degrees C group (1.37 times) were significantly higher than this. Even 60 minutes after the hyperthermia, the heat-treated groups maintained levels 1.7-2. 0 times higher. The uptake within the tumor was better in the 43 degrees C group than 45 degrees C group.

A phase II study of Vindesine (VDS) was carried out in 20 patients with carcinoma of the lung (14 adenocarcinomas, 3 squamous cell carcinomas, 2 large cell carcinomas and 1 small cell carcinoma), and in 18 patients with metastatic pulmonary tumor (primary organ: 4 colons, 2 uteri, 2 lungs, one each tongue, pharynx, maxillary sinus, esophagus, mediastinum, bile duct, pancreas, kidney, rectum and sarcoma). VDS was given weekly by i. v. push at a dose of 3 mg/m2. Patients should be given at least three times of VDS for eligibility. Of 18 evaluable patients with carcinoma of the lung, 3 patients with adenocarcinoma showed a partial response. Response rates were 17% for patients with carcinoma of the lung, and 25% for 12 patients with adenocarcinoma. Two responders (uterine cervical carcinoma and mediastinal embryonal carcinoma) were observed in 14 evaluable patients with metastatic pulmonary tumor. In addition, one patient with metastatic maxillary sinus tumor showed a minor response. Major hematologic toxicities of VDS were leukopenia (less than 4000 cells/mm3--92%, less than 2000 cells/mm3--28%), anemia (less than 10.0 g/dl, 38%) and thrombocytopenia (less than 10 X 10(4) cells/mm3, 11%). Major non-hematologic toxicities were numbness (24%), constipation (11%), anorexia (21%), fever (16%) and liver dysfunction (21%). The dose limiting factor of VDS was leukopenia.

Paraaminobenzoic acid-N-xyloside (K-247) is a new antitumor drug, which has no direct effect on immunologic status. Clinical trial of K-247 was performed in 8 patients with for advanced or recurred gastrointestinal cancer, who had short life expectancy. Oral administration of K-247, 600 to 900 mg/day, was carried out in combination with antitumor treatments using MMC, FT-207, 5-FU, PSK or irradiation. No toxic symptoms were observed in all patients. Of the 8 patients studied, one showed an encouraging response, while the remaining 7 patients were too far advanced to respond to these treatments.

Immunization with MMC-treated EL-4 tumor cells could raise cytotoxic activity of non-adherent PE cells and resistance against rechallenge with small or medium doses of viable tumor cells. Administration of PSK augmented the generation of cytotoxic lymphocytes and the induction of resistance against rechallenge in mice immunized with such MMC-treated tumor cells. Augmented generation of cytotoxic lymphocytes may be ascribed to systemic effects of PSK but not to local effects in the peritoneal cavity, since augmenting effects of PSK were observed not only after intraperitoneal administration but also after oral administration. Either after intraperitoneal administration or after oral administration cytotoxic activity was detected in PE cells but not in spleen cells. Cytotoxic activity was detected in PE cells but not in spleen cells after intraperitoneal injections of MMC-treated tumor cells. Cytotoxic lymphocytes appear to differentiate to their mature form capable of being detected by 51Cr-release test principally at the site of direct graft rejection. Intraperitoneal administration of PSK was more effective in the augmentation of cytotoxicity of PE cells than oral administration. PSK may be able to have contact with precursors of cytotoxic lymphocytes more efficiently after intraperitoneal administration. Immunity against syngeneic tumor cells appears to be effective in elimination of small doses of tumor cells but to be overcome by medium or large doses of tumor cells at the rechallenge. Administration of PSK increased the threshold number to be eliminated by immune hosts. This finding seems to be important in relation to augmentation of resistance against metastasis or local implantation with a limited number of tumor cells.

Macromomycin, a new antitumor antibiotic (NSC-170105) with significant antitumor activity in animal tumor systems, was administered to 18 patients in an exploratory study. The dose ranged from 1mg to 30 mg per body with a single dose was given. The toxic effects included delayed type leukopenia and thrombocytopenia with nadir of 4 weeks. Except mild upper GI disturbance, no pulmonary, cardiac, hepatic, renal or CNS toxicity was observed. No anaphylaxis was observed in this study. MTD of macromomycin considered to be 26 mg/m2 and optimal administration schedule will be 20 mg/m2 every 6 weeks. Antitumor activity was detected in one patient with ovarian carcinoma with MR in short period.

A combined therapy of pepleomycin (NK-613) and radiation was performed in 15 cases of esophageal and cancer. Twelve cases out of 15 were inoperable, and 3 cases were operable. NK-631 was administered by drip intravenous injection at a dose of 5 mg per day for 3 consecutive days weekly, aiming at total dose of 60-120 mg. Tumor regression rates, which were measured by planimeter on esophagogram, were 42-92% (mean 72%): two cases were more than 90%, and more than 50% in 12 cases. An average of the survival period of 15 cases was 57 weeks with 7 cases (46.7%) of 1 year survival, 2 cases (13.3%) of 2 year survival. The side effects of NK-631 observed in the present study consisted of fever 6, stomatitis 2, skin rash 2, and reversible pneumonitis 2. This study suggests that NK-631 exhibit remarkable anti-tumor effects on esophageal carcinoma, and seem to be less toxic.

Pulmonary toxicity due to antitumor agents, chiefly bleomycin pulmonary toxicity including clinical feature, histopathology, pathophysiology, biochemical changes, common clinical settings (risk factors), and prevention was reviewed. Moreover, pulmonary toxicity from methotrexate, busulfan, cyclophosphamide, mitomycin C, 6-mercaptopurine, nitrosourea and procarbazine was reviewed.

Microangiographic study was performed with ten human tumors serially transplanted into nude mice to clarify the role of tumor vessels on the chemosensitivity of the human tumors. Five gastric carcinomas, two colon carcinomas, one breast carcinoma, one cholangiocarcinoma, and one hemangiopericytoma were used for the experiments. Seven tumors revealed hypervascular network of vessels, whereas hypovascular patterns of tumor vessels were observed in the other three tumors. It was found that the histologically differentiated tumors were hypervascular and undifferentiated tumors were hypovascular, with statistically significant differences (p less than 0.05). Each tumor possessed the vascular network similar to human tumors originated from the same organs. No discernible changes of microangiographic features were noticed by serial transfers. As the chemosensitivities of these tumors depended mainly on their original tissues, these chemosensitivities could not be explained only by tumor vascularities or drug transferences. However, in the tumors with similar chemosensitive spectra, less susceptible tumors were observed to possess the irregular vascular networks in comparison with sensitive strains. From these considerations, tumor vessels were thought to have some role on vascular flow and drug transference which affected chemosensitivity of human tumors.

The Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer in Japan with the participation of 334 institutes nation-wide had conducted the secondary study in order to investigate the usefulness of futraful in long term treatment, based on the results obtained by the primary study. The following method was taken for the study and patients were randomly divided into three groups: A group-given a high dose of MMC immediately after operation; B group-given futraful for one year after MMC administration; C group-given futraful alone for long-term. The number of eligible cases for data analysis was 3,o30. Side effects observed during the long term treatment with futraful were considered to be minor. Although the occurrence of hematocytopenia was slightly frequent because of possible increase of influence by the concomitant use of MMC, no tendency of hepatic disorders and any subjective side effects to be strengthened by MMC combination was observed at all. As for 2-year survival, an elevated survival was found in the group of concomitant use of MMC and futraful; Especially, a significantly high survival was found in the cases of stage III and n (+) . ps (+). Furthermore, the survival was elevated in proportion to the increase of total dosage of futraful. This suggested the usefulness of futraful for long term treatment.

Maintenance treatment with FT-207 was applied to 92 patients with uterine cancers after initial treatments were performed. Daily dosage of FT-207 was either 600 or 800 mg and the drug was administered orally. The duration of 6 months and the total dosage of 100 g were proposed as administration schedule and 34 patients (37%) received this regimen. Side effects during the treatment were observed in 35 cases (38%). Gastrointestinal disturbance was most frequently observed and other side effects included myelosuppression, general fatigue, hepatic dysfunction and skin toxicities. There were no serious side effects, the treatment was continued in most patients and was interrupted only in 7 cases (8%). In the cases of recurrence or advanced cancer, however, the side effect was the predominant cause for interruption of administration. As for the antitumor effect of the treatment, a survival rate of the patients with cervical cancer of early stages was evaluated. Three-year survival rate in the treatment group was higher comparing to the one reported hitherto.

Malignancy and antigenicity of fibrosarcoma Meth 1 cells induced in a BALB/c mouse were compared with sarcoma Meth A cells. Furthermore, antitumor effect of levamisole (LMS) against Meth 1 cells and its immunological mechanism were studied. 1) The lifespan of BALB/c mice inoculated i.p. with 10(2) Meth 1 cells was prolonged by the treatment with LMS. 2) Growth of s.c. inoculated secondary tumors was tumor-specifically inhibited in solid Meth 1-bearing mice as compared with that in non-tumor-bearing mice. Administration of LMS (0.625 or 2.5 mg/kg) augmented the growth inhibition of these secondary tumors. 3) Spleen cells of Meth 1-bearing mice showed a growth-inhibitory activity against Meth 1 cells in Winn assay. LMS (0.625 or 2.5 mg/kg) augmented such a growth-inhibitory activity of spleen cells. The activity was attributed to non-adherent, thy 1-positive spleen cells.

An antitumor activity of macromomycin, a polypeptide antitumor antibiotic, was tested in vitro and in vivo. The results obtained were as follows: 1) The cytostatic effect on L1210 cells in culture was identical to that of neocarzinostatin. 2) The effect of MCR on the survival of L1210 or P388 leukemia was as same level as NCS. 3) Effects of MCR were independent from the treatment schedules. 4) MCR was inactive on the survival of Lewis lung carcinoma.

The experimental and clinical effects of bestatin were examined and the results obtained were as follows. Bestatin which is an immunomodulator discovered by Umezawa did not increase the bone marrow stem cells examined by the method of the spleen colony assay in the 60Co irradiated mouse. However, it prolonged the survival time slightly when it was administered 10-25mg/kg intraperitoneally. Clinically, bestatin was administered to the patients with gastrointestinal cancer. It did not influence on the PHA-induced lymphocyte blastformation rate, but it increased the peripheral lymphocyte count and PPD skin reaction in the cases of curative resection and increased the peripheral lymphocyte counts in the cases of nonresection after 1 month of the operation.

Comparative study of antiemetic effect on vomiting due to cancer chemotherapy was performed in 62 children with various malignant diseases. Twenty-one children were treated with metoclopramide, 23 children with domperidone and remaining 18 children received methylprednisolone. Each drug was administered intravenously after administration of anticancer agents, and repeated if necessary. The most effective antiemetics was methyl-prednisolone with effective rate of 89% in comparison with 51% of domperidone and 17% of metoclopromide treated group, respectively. Methyl-prednisolone may be useful for severe vomiting due to anticancer drugs. Safer and significantly better therapeutic efficacy was observed in the group treated with domperidone than that with metoclopromide.

A preliminary use of Peplomycin (PEP) was investigated in 14 patients with advanced esophageal cancer. PEP was given intermittently with a dose of 10 mg intravenously twice a week. As side effects there were observed fever elevation in 8 cases, stomatitis in 4 cases, erosion of the skin of the scrotum in 1 case and pigmentation in 1 case, respectively. Dyspnea associated with decrease of PaO2 was observed in 4 cases, which recovered promptly after discontinuing of the administration. Out of 10 evaluable cases, partial response was observed in 1, minor response in 1, no change in 3 and progressive disease in 5 cases, respectively. While the effect was only limited in these experiences, the local injection of PEP into or around the tumor using the external fistula of the remaining esophagus which was made at the time of by-pass operation was discussed.

It has been suggested that flow cytometric analysis may offer an ability to select drugs for chemotherapy of malignant neoplasms. For this purpose perturbation of cell cycle travers which induced by several anti-cancer drugs were studied to determine the fundamental factors to evaluate the effectiveness of therapy for individual tumors. From these results, we have made a presumption that for the majority drugs studied, the perturbation of cell cycle travers will be proportional to tumor cell kill. Primary cultured cells from the human brain tumor were used to determine the effectiveness of drugs for its treatment using Factor B (the accumulated cells in SG2M phases after anti-cancer drug treatment as the percentage of cells that was previously in SG2M phases) in comparison with the results (dose-response curves) obtained by glioma cell line. The clinical application was tried using these results. A case with malignant astrocytoma had shown 20.8% for ACNU treatment, however, 85.7% for VCR treatment in maximum range of Factor B on the samples of the removed tumor at the operation (cultured cells). This patient was already treated with radiation, ACNU and other anti-cancer drugs but subsequently failed and revealed constant growth in tumor size. Thereafter patient was treated with VCR according to flow cytometric indication, there was a response, that was the first time after the desperate trials of various drugs. It was only one case, nevertheless, this result illustrates the type of studies for our plan to pursue in order to determine if flow cytometric analysis aids in the brain tumor chemotherapy by individualizing patient's treatment in near future.