A new fluorinated pyrimidine, TAC-278, was studied for its safety, anti-tumor activity and pharmacokinetics in patients with solid tumors of various types. Single oral administration was done in 43 patients with dose range of 50 to 1200 mg. These single administrations caused no side effects but nausea in only one patient daily given 900 mg. Repeated oral dose tolerance was assessed in 79 patients in daily doses of 100 to 1800 mg. Side effects were reported by 26 (33.3%) of the 79 patients. Major side effects were mild gastrointestinal symptoms. The maximum tolerated dose was considered to be 1200 mg/day, over which CNS symptoms as dose limiting factor for TAC-278 developed in some patients. As to the therapeutic effect, minor response was obtained in 2 of the 24 evaluable patients. Concentration of 5-FU in body fluid and tumor tissues were high following oral administration of TAC-278, but the disappearance was relatively rapid. Excretion of TAC-278 occurred predominantly in urine.

Reports of intra-arterial infusion chemotherapy for carcinomas were reviewed and the role of intra-arterial chemotherapy was discussed. Thirty-four patients with urogenital cancers, 27 of bladder transitional cell carcinoma, 5 of renal cell carcinoma and 2 of prostatic adenocarcinoma, were treated with adriamycin artery infusion and the pathological evaluation was performed. A response rate of the treatment for bladder cancer was 50.0%.

Although transurethral resection seems to be the primary modality in the treatment of low grade & low stage bladder carcinoma, there are circumstances in which an effective intravesical chemotherapeutic drug could be incorporated into the therapeutic modality. Intravesical chemotherapy do not any special instrument and not require great skill. Additionally, now many chemotherapeutic agents which show cytocydal effect on bladder carcinoma after a brief time instillation, can be obtained. Therefore, intravesically chemotherapy has come to be used routinely. Thio-TEPA, mitomycin C and adriamycin are most frequently used for intravesical chemotherapy and the therapeutic effectiveness has been reported. The optimal intravesical chemotherapeutic drug should possess the following properties: (1) sensitivity to transitional cell carcinoma (2) efficacy after a brief contact (3) low absorption from the bladder (4) low irritable action to the normal bladder mucosa Adriamycin meets these demands except (4), and shows clinical response by fewer instillation than thio-TEPA & mitomycin C. A 68% effectiveness has been experienced by six to nine times of instillation (adriamycin 50mg/normal saline 30ml). Carboquone, cytosine arabinoside aclacinomycin A. bleomycin and neocarzinostatin are also used. Although these intravesical chemotherapy is evaluated with the combination of hydrostatic pressure therapy and irradiation, these modalities still seem to need further study.

Anthracycline antibiotics are principal agents in the treatment of acute non-lymphocytic leukemia, although the usefulness are limited by their adverse side effects, especially by the cardiotoxicity. Aclacinomycin A (ACM) is known to be a new anthracycline antibiotic which has been isolated from Streptomyces galilaeus, and its cardiotoxicity on the experimental animal systems was reported to be more than 10 times lower than that of adriamycin. We investigated the cardiotoxicity of ACM on 29 patients with acute leukemia and compared it with daunorubicin (DNR). The measurement of STI (PEP:LVET) has been recommended to be convenient method of assessing the anthracycline cardiotoxicity, but through out analytical study, QTC measurement was proved to be more valuable for the simple and rapid detection of the cardiotoxicity induced by the agents. In comparison with the QTCs in DNR and ACM, the cardiotoxicity of ACM was much lower than that of DNR, and the reversibility of ACM induced cardiotoxicity was much more rapid. Moreover, these effects were observed even in the patients treated with the maximum dose of DNR. Therefore, ACM was expected to be one of the agents of the first choice for the relapsed cases of acute leukemia, especially APL.

UFT (a mixture of futraful and uracil) was administered orally to 15 cases of recurrent and superficial bladder cancer principally for more than 4 weeks at the doses of 300 or 600 mg per day. The result was evaluated by Koyama-Saito's response criteria. Of 14 evaluable cases, complete remission was noted in 5. Two cases of advanced bladder cancer were treated with UFT combined with irradiation therapy, and one case was found that cancer cells degenerated severely in the primary lesion pathologically. Another case was recognized that lung metastasis disappeared completely. As the side effects, anorexia occurred in 2 cases with 600 mg per day and 1 case with 300 mg, but it was not so severe to terminate UFT therapy. From above-mentioned results, UFT seems to be a useful drug for the treatment of bladder cancers.

In 26 patients with cancer of the stomach, bone marrow function, cell mediated immunity and plasma CEA level were examined after administration of ACN-U. ACNU was given intravenously and intermittently with 5-FU given orally daily. Results 1) Delayed myelosuppression was observed in every cases and reached to the nadir in 2-7 weeks after ACNU administration. 2) Bone marrow suppression and recovery therefrom were observed earlier in platelet counts than in RBC and WBC counts. 3) Suppression of cell mediated immunity was not observed later than 4 weeks after ACNU administration. 4) Plasma CEA level decreased or stopped to increase after ACNU administration in 5 out of 8 patients having a high CEA level before treatment. 5) Regression of tumor size was observed in 4 out of 5 patients in whom a tumor was palpable. Conclusion ACNU has a strong antitumor activity and may be more effective if combined with antimetabolite agent, such as 5FU. Total dosage of ACNU given safely in one series was considered to be 150-200mg. Next series of ACNU administration should be started after restoration of platelet counts more than 100,000/mm3 was obtained.

Thirty patients with gastric cancer were clinically studied by rectal administration of FT-207 suppository at a dose of 1500mg per day as a preoperative adjuvant chemotherapy. Eighteen of thirty patients were divided into two groups, 13 patients of which were only administrated with tegafur (FT-207) suppository (Group A) and 5 patients were administrated with glutathione (GSH) at a dose of 1200mg daily with FT-207 suppository (Group B): The tissue concentration of FT-207 and 5-FU in normal and cancer tissues was measured following the resection of the stomach. In addition, we studied anticancer effect of FT-207 suppository on the basis of our original pathological criteria. Experimental results revealed that 5-FU concentration in serum was reached to maximum at 3 to 4 hours following administration in both groups. The serum concentration in most cases of the former group was decreased to the lower level of the effective concentration for 8 hours, however the latter could be kept the effective concentration for more than 10 hours. The correlation between the tissue concentration and total dose was analyzed. 5-FU concentration, which was active substance of FT-207, in cancer tissue was higher than in normal one, especially in Borrmann II type cancer, but the difference of concentration was not found between group A and B. The correlation between total dose and anticancer effect was also analyzed. Histopathological effect in group A showed a mild change, such as necrosis of cancer nest. On the other hand, group B revealed a markedly effective change like scarring formation. As the result, administration of FT-207 suppository with GSH was clinically and histopathologically effective procedure as preoperative adjuvant chemotherapy.

The effect of Tegafur (FT-207) by oral administration on the development of urinary bladder tumors in Wistar strain male rats induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) was studied. Urinary bladder tumors were induced in 18 of 20 rats (90.0%) when rats were given 0.05% BBN in the drinking water for 8 weeks and then given water without BBN for 12 weeks. When FT-207 100mg/kg B. W./day was given in their diet after treatment with 0.05% BBN for 8 weeks, tumors developed in the urinary bladder with low incidence (9 of 16 rats: 56.3%). Hematotoxicity was not observed in all animals treated with FT-207. These results shows that FT-207 also inhibited the development of urinary bladder tumors treated with BBN in rats by oral administration, which were similar those our previous results showed by intraperitoneal administration of FT-207.

Chemotherapy of advanced bladder cancer aims to destroy all the cancer cells in the host. For this purpose the most suitable and effective anticancer agents should be chosen. There have been many methods to select the anti-cancer drugs: sensitivity test. However, no reliable tests are available. We developed new anti-cancer sensitivity test, using the radio-active nucleic acids precursors; C14-Formate and C14-Adenine. This test revealed that Cisplatin, Adriamycin, and Mitomycin C were the most potent for the transitional cell carcinoma of the urinary bladder. Chemotherapy with a single agent was disappointing. Combined use of these agents was rather promising. Among them combination of cis-platin with Adriamycin and/or cyclophosphamide was the most effective. However, the overall response rate was reported around 50%. Multi-disciplinary treatment including surgery, irradiation, chemotherapy, and immunotherapy was disclosed to be useful for the treatment of bladder cancer. Since 1977 25 cases were treated with this mode of therapy in our clinic. Anti-tumor effect was remarkable. The categories, disappeared, and over 50% decrease of the mass, were found in 96% of the patients. Also, down-staging was demonstrated in 20% of the cases. Histologically no cancer cells were found in the surgical specimens of 3 cases and no viable cancer cells in 3 cases respectively. From these results it is now assumed that multi-disciplinary treatment is promising for the treatment of bladder cancer.

The effect of preoperative bladder instillation (POI) and periodic prophylactic bladder instillation (PPI) of anticancerous drugs was evaluated in connection with the prevention of recurrent bladder tumors after surgery. A total of 191 patients with pTa or pT1 tumors including patients submitted to TURbt and partial cystectomy from January, 1967, to December, 1980, was chosen for the study. They were divided into the following 4 groups: Group A (49 cases) was treated with PPI and POI, Group B (11 cases) with PPI but not POI, Group C (46 cases) with POI but not PPI and Group D (85 cases) with neither PPI nor POI. POI was performed three times a week for a total of 20 applications of anticancerous drugs from two months before surgery. PPI was performed twice a month from one month after TURbt or parital cystectomy with a combination of 20mg of Mitomycin C and 1,000mg of 5-FU. The non-recurrence rate in these 4 groups was estimated by the actuarial method. The 3 year non-recurrence rates in Groups A,B,C and D were 95.4%, 90.9%, 44.0%, and 45.6%, respectively. The 5 year non-recurrence rates in Groups A,B,C and D were 82.4%, 81.0%, 32.0% and 35.1%, respectively. It is presumed from our study that PPI was effective in preventing the recurrence of bladder tumors. In comparison, POI showed a very limited effect and only in the first two years after surgery. No carcinogenic action on the bladder epithelium was observed from the topical use of Mitomycin C.

Though a variety of treatments have been employed as an adjuvant for renal cell carcinoma, none of them has proved to be significantly effective, suggesting the difficulty in the treatment of this disease. The transcatheter arterial chemoembolization utilizing mitomycin C microcapsules developed by us was applied to renal cell carcinoma with an attempt at enhancing the chemotherapy and embolization. The early results indicate that this mode of treatment facilitates radical nephrectomy due to its marked antineoplastic effects and provides a favourable prognosis in locally advanced renal cancer. The experimental and clinical profiles of intra-arterial microcapsules were presented.

Twenty-two patients with malignant lymphoma and its allied diseases, consisting of 6 with Hodgkin's disease, 10 with non-Hodgkin's's diffuse lymphoma, 4 with leukemic lymphosarcoma and 2 with immunoblastic lymphadenopathy, were entered into this study. The treatment schedule was intravenous drip infusion of the drug, at a dose of 2.3 to 5.4 mg/kg (150 mg to 300 mg/day), for consecutive 4 to 14 days. The total dose given ranged from 1050 to 2500 mg. Four of the 6 patients with Hodgkin's disease and 5 of the 10 patients with non-Hodgkin's diffuse lymphoma showed a good response. The response started from 3 to 7 days after beginning of BH-AC administration and remission induced by BH-AC persisted for 4 weeks. Clinical toxicities such as anorexia, nausea and vomiting were very mild, but hematological toxicities such as thrombocytopenia, leukopenia, and anemia were frequent especially in the patients who were totally given more than 2100 mg. This study suggested that malignant lymphoma responded definitely to single administration of BH-AC and that BH-AC might be a new useful drug for multi-combined chemotherapy of malignant lymphoma.

This article is a review of the results of chemotherapy for advanced hormonally-unresponsive prostatic carcinoma. Although the only hope for treatment of these patients is chemotherapy, until recently relatively little emphasis has been placed on chemotherapy of prostatic cancer. Since results of the randomized trial of the National Prostatic Cancer Project in the United States revealed a demonstrable advantage of advanced hormonally-refractory disease, a number of studies has been done and reported. As single chemotherapeutic agent, cyclophosphamide (CPM), 5-fluorouracil (5-FU), Adriamycin (ADM), and Cisplatinum (CDDP) have activity in these patients. Estracyt has been reported very effective, but has been somewhat disappointing in American trials. Several combination chemotherapies have been reported effective, such as CPM + ADM, CPM + ADM + Methotrexate (MTX), and CPM + MTX + 5-FU + Vincristine, Prednisone. Presently, however, there is no evidence that combination chemotherapy in prostatic cancer is better than single-agent chemotherapy. The need for continued effort to search powerful new agent, and to establish more effective combination chemotherapy for prostatic cancer should be emphasized. Furthermore, the importance of randomized and stratified clinical trials, early and late in the course of the disease, is stressed.

Tegafur fine granule preparation orally administered to the patients with primary hepatoma and liver cirrhosis, and the concentration of tegafur and 5-fluorouracil in the blood were determined. The concentration of tegafur in blood was maintained well in the injured liver, and remained same 3 weeks after administration of tegafur fine granules. The concentration of 5-fluorouracil in the blood decreased distinctly when the dysfunction of the liver was severe (KICG less than 0.070). In the case of malignant disease with the injured liver, oral administration or tegafur might be less effective. However, the concentration of 5-fluorouracil in the blood did not decrease 3 weeks after administration of tegafur fine granules. No cases showed noticeable clinical effects by only oral administration.

Survival period of 28 cases with unresectable hepatocellular carcinoma treated with transhepatic arterial one-shot infusion of 30 mg mitomycin C (MMC) were retrospectively reviewed from the standpoint of hepatic angiographic findings, scintigraphic existence of liver cirrhosis and changes of AFP value. As the result, 17(61%) of 28 cases survived 6 months after treatment. As to the angiographic findings, no remarkable differences on the survival period was noted in both of less and/or more than 50% of the tumor extent occupied on hepatic angiogram, and relatively long-term survivors were seen in the cases without A-V shunt and invasion of portal veins. Concerning association with liver cirrhosis, the survival period was not dependent on the presence of liver cirrhosis on the scintigrams. Regarding the changes of AFP value before and after treatment, no survivor over 6 months was encountered in the cases which revealed an increasing value of AFP. It may be considered that hepatic arterial one-shot infusion of MMC should be attempted in the unresectable and advanced hepatocellular carcinoma, even though palliative treatment.

Eighteen previously untreated patients with squamous cell carcinoma of the lung were treated with a combination of a new bleomycin derivative, peplomycin and esquinon (PQ). One patient achieved a complete response (5.5%) and 5 patients a partial response (27.8%). Overall response rate was 33.3%. Median survival time of 6 patients with complete and partial response was 54 weeks and that of 12 patients with no change and progressive disease was 15 weeks. Toxicities included nausea and/or vomiting in 89%, fever in 61%, interstitial pneumonitis in 28% and leukopenia in 17%. PQ regimen appears to be effective in the treatment of squamous cell carcinoma of the lung.

The serum concentration of HCFU and its metabolites was clinically studied to obtain the most useful information for optimal methods of oral administration of a new anticancer agent. In this paper, the serum level of the only 5-FU among metabolites of HCFU was discussed. High-performance liquid chromatography was used as monitoring the agent. The serum level of 5-FU usually reached a maximum one hour after oral administration of 200mg HCFU and remained more than 0.2 to 0.3 microgram/ml for at least two hours. When administered 200mg HCFU every 6 hours (800mg/day), the serum level of 5-FU could be maintained more than 0.1 micrograms/ml for 24 hours. When administered 200mg three times after each meal (600mg/day), its level could be maintained more than 0.1 microgram/ml only for daytime, but not at night. Consequently, we suggest that the most favorable therapeutic oral administration of HCFU might be 200 mg every 6 hours (800mg/day) to maintain the serum level of 5-FU over 0.1 microgram/ml for 24 hours.

Poorly radiorespondent and upanhysterectomized 10 cervical cancer patients, 2 being Stage IIb, 6 Stage III and 2 Stage IV, underwent a modified pelvic vascular bed isolation chemotherapy with one shot infusion of 50mg to 70mg of mitomycin C: into the internal iliac arteries. In 9 cases out of 10 thus treated, cytological, histological and macroscopic examinations failed to detect local malignancy after the isolation chemotherapy. However, there was a notable time difference in disappearing their local malignancies. Namely, 5 cases needed less than 15 hours to expel their cytological local malignancies, while the other 4 cases needed 4 days or more, average 13 days. Two cases needed less than 15 hours to eliminate their histological local malignancies, while the other 7 cases 3 days or more, average 10 days. Only 5 patients whose cytological malignancy disappeared within 15 hours are now all alive without apparent disease since the past 10 months or more, average 31 months. On the other hand, 4 patients who needed 4 days or more and 1 patient whose local malignancy was maintained even one month after the isolation chemotherapy were all dead with average survival period of 7.6 months in spite of the additionally performed excision surgery. It is concluded here that the modified isolation chemotherapy will be able to eradicate almost all evidences of local malignancies, no matter how obstinately the tumor resists to radiotherapy. However, cytological evidence of local malignancy ought to be eliminated within 15 hours in order to ensure elongation of patient's survival period.