Thirty-nine patients with superficial bladder cancer underwent intravesical instillation therapy of Aclacinomycin-A (ACM). Antitumor effect of ACM was evaluated in 19 patients and objective responses (CR + PR) of tumor were observed in 84.2% of these patients. Prophylactic instillation therapy of ACM was carried out on 20 patients and the results were compared with those obtained for 10 control patients who had first episode of bladder tumor and received no instillation therapy. No significant difference in the recurrent rate was observed between these two groups. The major side effect for instillation therapy with ACM was bladder irritation which appeared in 38.5% of all the patients.

Recently, there has been much concern that cancer chemotherapy may have undesirable consequences in the form of secondary malignancies. At present, secondary leukemia or therapy-linked leukemia constitutes a well delineated clinical syndrome characterized by several distinct symptoms, that was illustrated by the presentation of cases recently observed. In an attempt to understand the basis for this therapy-linked leukemia, mutagenic activity of various anticancer agents were studied by the induction of sister chromatid exchanges and risk of a certain drug as a possible candidate causing secondary leukemia was discussed from the molecular cytogenetic point of view. From both clinical and cytogenetic aspects it seemed that bifunctional alkylating agents were potentially relevant to the development of secondary leukemia.

We treated 27 patients with far-advanced cancer with extracorporeally induced total-body hyperthermia combined with anticancer chemotherapy (TBHC). All of them under went unsuccessful anticancer chemotherapy. Excluding 7 patients who could not be evaluated, a partial response was obtained in 7 of 20 patients (35%). Considering that the patients in our series were in the terminal stage of cancer, our results are encouraging. However, despite the regression of the mass in some patients, the survival time after TBHC was not always prolonged. A characteristic complication of TBHC was the weakness of the muscles in the lower extremities. The occurrence of muscle weakness could be prevented by administration of phosphate. To improve the therapeutic effects of TBHC, there are some problems to be solved. In combined anticancer chemotherapy, the selection of anticancer drugs and the timing of their administration are of importance. Thus, the optimal heating method and the combined anticancer chemotherapy are the areas requiring further study to determine the clinical efficacy of TBHC in patients.

In order to obtain less severe toxic reactions and maximal therapeutic effects, 729 patients with cancer of the liver or biliary tract or pancreas were treated with intra-arterial infusion of 5-FU and mitomycin C (MMC) alone or in combination with 2450 MHz microwave hyperthermia. Approximately 60% of the patients with primary hepatic cancer showed objective response to the intra-arterial infusion of 5-FU and MMC. However, many patients developed hemorrhage of esophageal varices, gastroduodenal ulcers, jaundice and ascites because of high incidence of hepatic cirrhosis with hepatoma. Fifty percent survival period was only 5.2 months and 26% of the patients so treated survived a year or longer. Metastatic liver cancers, on the contrary, showed better results as compared to those of the primary liver cancer. Fifty percent survival period for metastatic liver cancer was 8.0 month and 42 percent of the patients survived a year or longer. For the cancer of head of the pancreas, the combination of intra-arterial infusion chemotherapy and microwave local hyperthermia was proved to be the most effective way to control cancer. Nine patients before 1975 were treated with intra-arterial infusion chemotherapy alone and 25 patients in and after 1975 were treated by intra-arterial infusion chemotherapy in combination with hyperthermia.(ABSTRACT TRUNCATED AT 250 WORDS)

A phase I-II study of KW2083, an analog of mitomycin C (MMC) was performed in a total of 22 patients. KW2083 was escalated by single intravenous administration of 40, 50, 60, 70, and 80 mg/m2 doses. Treatments were repeated every 4-6 weeks unless unacceptable toxicities occurred. The median times taken to reach nadir for each dose level were 9-12 days for leukocytes and 7-13 days for platelets respectively. The median times taken for recovery were 8-22 days for leukopenia and 10-37 days for thrombocytopenia. Variable and non-predictable hematological toxicity was observed in some cases. Biphasic hematological toxicity was observed in 4 courses. Acute toxicity occurred in 17 courses for 11 patients and consisted of nausea (44%), vomiting (13%), diarrhea (2.7%) and stomatitis (2.7%). Nephrotoxicity (elevation of BUN, 8.1% and proteinuria, 5.4%) occurred in 3 patients who had no previous impairment of renal function. Alopecia (8.1%) was also observed. Marked elevations of hepatic enzymes were noted in one patient who developed acute fulminant hepatitis with the second dose of KW2083. Objective response was observed in one of 20 evaluable patients. From this preliminary study, the maximum tolerable dose is 70 mg/m2 and the optimal dose of KW2083 was determined to be 50 mg/m2 at 6-week intervals. KW2083 has been introduced as an MMC analog of potential interest. However, hematological and non of hematological toxicities are very similar to those of MMC and does not appear that KW2083 will supersede MMC.

The anti-tumor effect of twice a week instillation of 30 mg mitomycin C combined with 200 mg cytosine arabinoside dissolved in 30 ml saline was studied in 37 bladder tumor patients. Endoscopic or histological disappearance of the tumor was observed in 19 cases, average instillation being 16.4 times. Small (less than 1 cm in diameter), low grade, low stage and villous-surfaced tumors were more sensitive to this therapy. Further more, in the cases showing a complete response, frequency of the intravesical tumor recurrence significantly decreased compared with the cases showing no response. The clinical results of this therapy are compared mainly with those of TUR performed at our hospital, and the usefulness and clinical limitation of this kind of management in the treatment of bladder tumors are discussed.

Anti-cancer drugs in the forms of an emulsion, a microsphere, and of conjugates with high molecular dextran have been developed in our laboratories, namely a fat emulsion of anticancer drug, MMC-microsphere, or MMC-dextran conjugates. The main advantages of these forms of pharmaceutical preparation are that they give prolongation of pharmacological actions by slow release and that they are applicable for topical use because of their reduced toxicities to local tissue yet maintaining local therapeutic potency. In this study we found that the rate of sustained release of drugs and antitumor effects were enhanced when used in such modified forms of drugs for topical injections. Results of clinical trials of those drugs have been promising. However, the number of trials has been limited so far. Further studies would be required for evaluating on of their clinical utilities.

The influence of PSK on the metabolism of FT-207 was studied in patients with gastric cancer. The 5-FU concentration in the blood was determined 15 min, 30 min, 1 hour and 3 hours after intravenous injection of FT-207, 400mg. The blood level of 5-FU remained constant in 86% of patients after administration of PSK for 7 days, but decreased in 14% of patients. After administration of PSK for 8 to 14 months, no change in the blood level of 5-FU was detected. These results suggest that PSK has no distinct influence on the activation of FT-207.

Hyperthermia is being re-evaluated and currently used in the treatment of malignant tumor. There have been numerous in vitro and in vivo experimental data presented which confirm the selective heat damage on malignant cells. This review will attempt to summarize the information on experimental and clinical reports concerning hyperthermia. The results of extracorporeally induced hyperthermia of our series are also mentioned.

Chemotherapy using arterial infusion was employed to introduce an anti-cancer drug directly into the arteries which nourish the tumor, thereby distributing a high concentration of the drug to the tumor, increasing the anti-tumor effect and reducing the amount of the drug in circulation throughout the body, thus mitigating its side effects. However, the uptake of the anti-cancer drug into the tumor and its distribution throughout the body are influenced by a large number of factors: the method or route of administering the anti-cancer drug; rate of infusion; local blood flow; permeability of the blood vessels; structure and affinity of the drug; the metabolism of the drug and the speed of its breakdown and elimination. As long as this kind of pharmacokinetics is involved, the principal merit of the arterial-infusion chemotherapy is that the first time the drug is circulated, a high concentration is distributed to the arteries which feed the tumor. However, there is a great deal as yet unknown about the peculiarities and variability of anti-cancer drugs and the internal organs.

Selective deposition of lipiodol in primary and metastatic liver cancer, lung cancer, gallbladder cancer, pancreatic cancer and renal cancer was elucidated by plain X-ray film and CT. Selective delivery of anticancer agent, SMANCS was also proved by measurement of its biological activities of removed specimen. Because of these selective delivery of anticancer agent and embolization of neovasculature in the tumor, highly effective chemotherapy of unresectable cancer was established. Drug was given via celiac, the hepatic, bronchial or renal artery mostly 1-5 mg in 1-5 ml of lipiodol once every 3-8 weeks. Antitumor effects of this therapy for hepatocellular carcinoma was confirmed based on decrease in AFP levels (92% of the cases), reduction in tumor size (90% of the cases) and histology. In 76 percent of the patients with the other malignant solid tumors reduction in tumor size was recognized. Decrease in CEA level occurred in 88 percent of the cases with metastatic liver cancer and lung cancer. Major side effect was transient fever in about 50% of cases. Mitomycin C and aclarubicin dissolved in lipiodol showed remarkable antitumor effects for experimental liver cancer.

Four patients with urinary bladder carcinoma were treated by combination therapy which consisted of hyperthermia vesical irrigation of two anticancer drugs (peplomycin and picibanil), intravesical instillation of those drugs and radiation. Following the therapeutic method we planned, 40 mg of peplomycin and 10 KE of picibanil in 1,500 ml of sterile distilled water was irrigated at 42 to 43 degrees C into the bladder for 3 hours; 40 mg of peplomycin and 10 KE of picibanil in 40 ml of sterile distilled water was instilled into the bladder; and, the focus was irradiated with 60Co to a focal dose of 200 rad 30 minutes later. This pattern of treatment was repeated once a week, 3 to 5 times in total. On the days this pattern was not taken, 5 KE of picibanil in 20 ml of sterile distilled water was instilled into the bladder cavity. Complete response was observed in one patient and partial response in 3 patients. The side effect was temporary irritable bladder symptom.

Induction in vivo of resistance of C6 rat glioma and 9L rat glioma to ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride] was studied and ACNU-resistant rat meningeal gliomatosis models were developed by using these resistant glioma sublines. Rapid acquisition of resistance to the agent was present at 2nd transplant generation in both glioma lines. Cellular resistance to ACNU remained unchanged in the absence of drug over 5 transplant generations in vivo in spite of the fact that the drug treatment was discontinued at the 5th generation after a complete resistance was induced. On the other hand, the degree of resistance of 9L resistant subline established by only once ACNU treatment was found to be decreased after 5 transplant generations in vitro. Degree of resistance at the cellular level was observed with each subline by in vitro technique and compared with each other. Each subline was found to have different degree of resistance: 9L resistant subline showed higher resistance than C6 resistant subline, and the differences in degree of resistance between 9L resistant subline and C6 resistant subline were approximately 750 and 20, respectively, when they were expressed as ratios of IC50 (drug concentration for 50% growth inhibition) for the resistant subline to the original one.

The relationship between cell growth inhibitory effects and terminal differentiation-inducing effects of nine clinically active chemotherapeutic agents was evaluated using HL-60, a human acute myelogenous leukemia cell line. Continuous exposure to HL-60 cells of adriamycin, daunorubicin, mitoxantrone, m-AMSA, cytosine arabinoside, 6-thioguanine (6-TG), actinomycin-D (Act-D) and vincristine resulted in percentage increase of morphologically differentiated cells and phagocytic cells. Hydrocortisone at a concentration of up to 10(-4) M failed to produce this effect. Examination of actual numbers per flask of morphologically differentiated cells and phagocytic cells revealed, however, that all these agents except Act-D and 6-TG failed to produce a numerical increase in differentiated cells in comparison with those of control groups at day 6. Only Act-D and 6-TG were able to produce increases in the percentage, as well as actual number, of differentiated cells. These data indicate that the percentage increase in terminal differentiation-induced cells by certain chemotherapeutic agents is due not to their ability to increase differentiated cells but to their ability to inhibit the growth of primitive cells preferentially.

The antitumor effect of a new synthetic cord factor analogue, 6, 6'-Di-O-dacanoyl-alpha, alpha-trehalose (SS 554), was examined in vivo and in vitro. Remarkable life prolongation effects were observed after the intraperitoneal administration of SS554 at a dosage of 150 mg/kg in mice implanted with Ehrlich ascitic tumor cells. Using in vitro tests, the growth of various tumor cell lines i.e. Meth-A, EL-4, RL male-1, X5563, Raji and Jurkat were inhibited by SS554 at a 25 mcg/ml concentration. The mechanism of the direct antitumor activity of SS554 was studied using these tumor cell lines and bacterial cells. After treatment with SS554 at a 50 mcg/ml dose for 30 minutes, tumor cells and bacterial protoplasts but not intact bacterial cells were destroyed, indicating that SS554 causes the lysis of the membranes of these cells.