We conducted a prospectively controlled study of adjuvant immunochemotherapy for resectable lung cancer in 37 cases of the control group, in 34 cases of levamisole group and in 40 cases of OK-432 group. No significant difference was noted in patient characteristics of age, sex, histological type, stage, cure rate, etc. The survival rates were calculated by Kaplan and Meier method. Survival curves were measured by generalized Wilcoxon test and Cox-Mantel test. When the levamisole group and the control group were compared in terms of survival rate, a significant increase of survival curves of patients treated with levamisole was observed in surgicopathological stage III + IV and relative curative operation groups (p less than 0.05). The survival rate of levamisole group was higher than that of OK-432 group in patients of surgicopathological stage III and III + IV (p less than 0.05). There was no statistically significant difference between OK-432 group and the control group, when in survival rates.

The effect of levamisole HCL on advanced and recurrent breast cancer was investigated cooperatively by a randomized controlled study using envelope method. Patients with advanced and recurrent breast cancer who had showed either complete response or partial response to the previous CAF therapy (cyclophosphamide 100 mg/body/day p.o. from day 1 to 14, adriamycin 30 mg/body/day i.v. on day 1 and 8, 5-FU 500 mg/body/day i.v. on day 1 and 8) were entered in this study and divided randomly into a control group and a levamisole group. No further treatment was given to patients of the control group until they fell into progressive disease. Patients of the levamisole group were given the drug at a daily dose of 150 mg for 3 consecutive days every fortnight. Fifty-nine cases were entered in this protocol, but 9 cases of them were ruled out as exclusions or dropouts. Therefore, the number of eligible cases was 31 in the levamisole group and 19 in the control group. Both the duration of remission and the survival time were significantly (p less than 0.05) prolonged in the levamisole group compared with the control group. There was no difference in side effects between these two groups.

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 effect of fibrinolytic agents, Tissue Culture Urokinase (TCUK) and Urinary Urokinase (UUK), was investigated in a total of 146 patients with gastric cancer, pulmonary cancer or breast cancer who received various anti-cancer agents, mainly MMC, in combination with the fibrinolytic agents. Assessments were made according to the Koyama-Saito criteria. In order to maintain impartiality of this comparative trial, the drugs were randomly administered to the patients by a card system. The patients who died during the study were excluded from the analysis and the patients with colorectal cancer were also excluded because this disease was not included in the study protocol. As a result, 51 patients given TCUK and 50 patients given UUK (101 in total) were subjected to analyse. The response rate (CR + PR/No. of admitted patients) was 15.6% (8/51) for the TCUK group and 10.0% (5/50) for the UUK group respectively. The patients with measurable lesions in the TCUK group showed a response rate of 25.9% (7/27) and those in the UUK group, 14.3% (4/28). Side effects were observed in 52.1% of patients in the TCUK group and 47.9% in the UUK group. However, these symptoms were related to the anti-cancer agents. Neither a tendency to hemorrhage nor allergic symptoms occurred in association with the two fibrinolytic agents, TCUK and UUK. to UUK in terms of an activity to enhance the chemotherapeutic effect of anti-cancer agents and that combination use of TCUK and anti-cancer agents seems to be useful.

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.

Pharmacokinetics of MMC was studied by bioassay method in cancer patients and experimental animals, and they were compared with those of a new mitomycin derivative, KW-2083. The blood level of MMC decreased relative by rapidly, t 1/2 beta in iv dose of 30, 20 and 10 mg/body to man was 50, 41 and 33 minutes, respectively. The drug level was able to increase locally by employing perfusion, arterial infusion, hemi-upper body infusion and intra-cavitary injection. The tissue level of MMC was high in the lung, kidney, muscle and skin, and moderate in the tumor of S180 bearing mice. MMC was inactivated strongly in the homogenates of the liver and kidney, and moderately in the heart and intestine of human tissues. The inactivation was enhanced by the addition of NADPH, vitamin B6, glutathione, etc. The blood level of KW-2083 in patients and mice decreased more rapidly than MMC. T 1/2 beta of KW-2083 in patients after iv injection at 70, 40 and 20 mg/body was about 18 minutes. The tissue level of KW-2083 in S 180 bearing mice was the highest in the lung and skin, followed by the kidney and tumor. The elimination rate of the drug from each tissue was more rapid than that of MMC. KW-2083 was highly excreted into the bile and more highly inactivated in the homogenates of the liver, kidney, muscle, etc. as compared with MMC. These pharmacokinetic behaviours of KW-2083 might be related to the lower toxicity and higher therapeutic ratio in experimental animals.

Therapeutic effects of PEP-AC and PEP-saline on pulmonary growth of intratracheally implanted tumor and metastasis into the hilar lymph nodes were studied in mice. Pharmacokinetic studies of PEP-AC and PEP-saline were made by autoradiography (ARG) using 3H-PEP and microbial assay method using B. subtilis. The ARG using 3H-PEP-AC and 3H-PEP-saline demonstrated qualitatively slower elimination of PEP-AC from mouse lung than that of PEP-saline. The half-life time (t1/2) of PEP-AC was estimated to be about 3 days by bioassay method, while about 60 min. was given for PEP-saline. Intratracheal administration of PEP-saline produced no therapeutic effect to pulmonary growth of B16 melanoma, while that of PEP-AC gave a good response depending on doses. Furthermore, PEP-AC inhibited metastasis of B16 melanoma into the hilar lymph nodes. Better therapeutic effects were produced by PEP-AC when decreased inoculum sizes of B16 melanoma or P388 leukemia cells were transplanted.

Optimal dose schedule of administration of antitumor antibiotics-bleomycin, adriamycin and aclacinomycin A-was reviewed from a point of view of pharmacokinetics. In case of bleomycin, according to its fast disappearance from blood, fast and significant excretion into urine, cell-cycle-dependent antitumor action, fast repair of potentially lethal damage, and pulmonary toxicity due to damage in endothelium of pulmonary capillary caused by high blood concentration of bleomycin, continuous intravenous administration seems to be a useful method to prevent pulmonary toxicity and to enhance antitumor effect. In case of adriamycin, according to its cardiotoxicity due to damage in cardiac muscle cell caused by high blood concentration on adriamycin, drip infusion or weekly low dose schedule is a safe, effective therapy to prevent cardiomyopathy. In case of aclacinomycin A, based on the mechanism of action of its marked inhibition in RNA synthesis compared to adriamycin, daily administration for certain days is an effective method.

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.