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Relation between flow patterns and stratification process is investigated by the observed data in Lake Onogawa. Transition of the time-scale, 7hr., obtained from coherence of temperature-cross-spectrum and retention time estimated from velocimetry has good agreement to the flow patterns in the lake. The flow in the epilimnion has high-rate horizontal circulation because the lake is used hydropower generation. In the hypolimnion, sediment transportation is observed in closing stage of the fluid in 1995, July, in spite of the flow stagnant in the stratification season.

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.

BACKGROUND Although razoxane (ICRF-159), a derivative of bis(2,6-dioxopiperazine), has shown significant antitumor activity in several murine tumors, inadequate bioavailability has limited its clinical efficacy. Sobuzoxane (MST-16), another derivative of bis(2,6-dioxopiperazine), has shown activity against a broad spectrum of murine tumors and human tumor xenografts in nude mice and a lack of cross-resistance to vincristine, doxorubicin, cyclophosphamide, fluorouracil, etoposide, and mitomycin C. These findings suggest that MST-16 has a mode of cytocidal activity different from that of other antitumor agents. PURPOSE The present late phase II study was conducted to evaluate the clinical efficacy and toxicity of MST-16 in non-Hodgkin's lymphoma (NHL). METHODS As part of a multi-institutional cooperative study, we conducted a study of MST-16 in 27 patients with NHL who were assessable for drug efficacy and toxicity. MST-16, a bis(2,6-dioxopiperazine) analogue and an inhibitor of topoisomerase II, was administered orally at a dose of 1600 mg/m2 a day for 5-7 days at intervals of 2-3 weeks. RESULTS Response consisted of one complete remission and seven partial remissions in 27 assessable patients. Response was achieved at a median of 13 days (range, 9-62 days) after initiation of therapy and lasted a median of 46 days (range, 29-155 days). Major toxic effects were leukopenia in 70% of the patients, thrombocytopenia in 44%, and gastrointestinal disorders in 37%. CONCLUSIONS MST-16 was shown to be effective in NHL and deserves further clinical trial, since the drug shows little cross-resistance to available antitumor drugs. IMPLICATIONS Phase II clinical studies of MST-16 in treatment of breast cancer, gastric cancer, and adult T-cell leukemia and lymphoma are also being conducted in Japan. Future trials of combination chemotherapy using MST-16 with other antitumor drugs are warranted in view of the additive effects observed in studies of MOLT-3 cells and studies of L1210 leukemia in mice.

A problem related to the capacity of snow removing by flowing water in ditch is treated. In this experiment, crushed ice was used instead of snow. The scale of the region of separation has been measured for the various plane forms of the elbow parts of ditch. The rise in ditch stage has been analyzed theoretically, and compared with the experimental values. The both results agreed approximately. The energy losses of the flow on the elbow parts of ditch is estimated. The limiting conditions of crushed ice trasportation by flowing water through the elbow parts of ditch has been studied experimentally.

This paper describes thermal stratification in lakes, its property of flux by destruction, and water quality transportation from results observed in field survey for Lakes Hibara, Onogawa and Akimoto. Its main conclusions by the above-mentioned ways are shown in the following.On the Whole, these lakes shows clearly not only thermal stratification in summer but also its destruction processes with the fall of water temperature. These lakes indicate a similar tendency of formation of thermal stratification in the vertical direction. Lake Hibara has clear processes of thermal stratification and of its destruction. Lake Onogawa has a tendency toward water stagnation. Lake Akimoto has a remarkable distribution for turbidity in the vertical direction.

In boulder-bed streams, large boulders jutting through the river bed play important roles in resistance to flow.This paper deals with the drag force and the structure of flow around hemispherical roughness elements, which are models of large boulders. The separation length and the drag coefficient for a hemipherical roughness element were experimentally studied in the flows with various Froude number, spacings of roughnesses, or relative depth.

l-P-Z)-Arabinofuranosylcytosine-5’-stearylphosphate (fosteabine) was administered orally to patients with myelodysplastic syndromes (MDS); refractory anemia with excess of blasts (RAEB), RAEB in trans

Friction facter and boundary shear stress distributions are ditermined for rectangular channels of a wide renge of Reynolds number and a renge of width-to-depth ratios (B/H) 0.5 to 10. The influence of wall effect on the boundary shear and maximum-velocity point occuring below the water surface are examined. The boundary shear distributions of open channels are discussed indetailed. By using the maximum-velocity point, the calculation method of the boundary shear distributions are proposed.

Aclarubicin was evaluated in combination chemotherapy for adult acute myeloid leukemia in a randomized trial involving 58 institutions throughout Japan. Behenoyl cytosine arabinoside (BH-AC).daunorubicin, 6-mercaptopurine, and prednisolone (DMP) was compared with BH-AC.aclarubicin, 6-mercaptopurine, and prednisolone (AMP). In the 360 evaluable cases among the 433 cases enrolled, complete remission (CR) rates were 63.7% (116/182) for BH-AC.DMP and 53.9% (96/178) for BH-AC.AMP (P = 0.0587). Median survival periods and 7-year survival rates were 15.8 months and 19.3% for BH-AC.DMP and 9.5 months and 20.2% for BH-AC.AMP (P = 0.0091 according to the generalized Wilcoxon test [GW], P = 0.196 according the log-rank test [LR]). Median disease-free survival periods were 15.4 months for BH-AC.DMP and 14.1 months for BH-AC.AMP (P = 0.851 by GW, P = 0.439 by LR). Among the 346 cases of extramurally confirmed FAB subtypes, CR rates were 67.9% (19/28) with BH-AC.DMP and 31.8% (7/22) with BH-AC.AMP for subtype M3 (P = 0.011) and 63.3% (93/147) with BH-AC.DMP and 56.8% (84/148) with BH-AC.AMP (P = 0.254) for subtypes M1, M2, M4, and M5. Diarrhea, ileus, pneumonia, and renal failure were more frequent with BH-AC.AMP than with BH-AC.DMP. The results indicate, at least on the basis of the long-term outcome, that BH-AC.AMP has antileukemic effects on subtypes M1, M2, M4, and M5 that are comparable with those of BH-AC.DMP.

A randomized clinical trial of combination chemotherapy for adult acute lymphoblastic leukemia (ALL) with doxorubicin, vincristine and prednisolone with and without L-asparaginase (AdVP vs L-AdVP) was conducted, involving 58 institutions throughout Japan. After reaching complete remission (CR), patients were treated with the same regimen for more than 2 years. Among 166 evaluable cases of the 198 cases enrolled, CR rates were 63.1% (53/84) with AdVP and 64.6% (53/82) with L-AdVP (P = 0.837). Median survival times and 7-year survival rates were 12.7 months and 21.2% with AdVP, and 16.0 months and 22.3% with L-AdVP (P = 0.955 by generalized Wilcoxon test [GW], P = 0.952 by log-rank test [LR]). Median disease-free survival times and 7-year survival rates were 13.5 months and 23.8% with AdVP and 17.0 months and 30.6% with L-AdVP, showing some increments for L-AdVP but no statistical significance (P = 0.141 by GW, P = 0.300 by LR). Among the cases of extramurally confirmed FAB subtypes, CR rates were 75.9% (63/83) for the L1 subtype and 51.3% (39/76) for the L2 subtype (P = 0.001). As to adverse effects, pancreatitis was complicated more frequently in L-AdVP than in AdVP (P = 0.039). Other side effects such as hyperbilirubinemia, diabetes mellitus, diarrhea and hypofibrinogenemia were observed more frequently with L-AdVP, but with no statistical significance. Thus, addition of a single course of L-asparaginase in the induction phase of combination chemotherapy with doxorubicin, vincristine and prednisolone did not significantly enhance the effect of antileukemic treatment of adult ALL.

Episodes of septicemia (114) in patients with solid cancers at Nagoya Memorial Hospital were analyzed from April 1985 to June 1986. The underlying malignancies were predominantly gastric and colon cancers. Almost all the cancers were in advanced stages, the most frequent patient performance status being 4. Hypogammaglobulinemia and granulocytopenia were not, however frequent among these patients. The major microbes detected from blood cultures were Candida sp., Staphylococcus aureus and Staphylococcus epidermidis. Preceding chemotherapies were mainly combination chemotherapies containing Cisplatin (CDDP). The major pathogen, Candida sp., was detected frequently from Hickman's catheter. Thirty-one percent of patients died within 14 days of the septicemia diagnosis (two were cases of septic shock).

A Phase II study of interferon alfa-2a was conducted in 64 patients with multiple myeloma (42 IgG, 16 IgA, 5 Bence-Jones type, and 1 IgD) in a multi-institutional cooperative trial. Partial remission was obtained in 10 (21.3%) of 47 evaluable patients, and minor responses in 5 (10.6%) of 47. Remission was reached at 22 to 89 days (median, 29 days) after the initiation of interferon alfa-2a and lasted 4 to 55 weeks (median, 8 weeks). Side effects were noted in more than two-thirds of patients, and included fever (58%), malaise (20%), anorexia (52%), nausea-vomiting (26%), lethargy (2%), and myelosuppression (56%). They were all reversible on discontinuation of interferon alfa-2a. Antibody to interferon alfa-2a was detected in 1 of 20 patients tested during the course of treatment. Thus, interferon alfa-2a was effective in multiple myeloma, producing unequivocal response in 21.3% of patients without unacceptable side effects.

The pharmacokinetics of carboplatin were investigated in cancer patients after single, IV infusion doses of 75, 150, 247.5, 300, 375, and 450 mg/m2. Total plasma and urine platinum and plasma ultrafilterable platinum concentrations were determined by atomic absorption spectrometry. Carboplatin was analyzed in plasma by a specific high-performance liquid chromatography (HPLC) procedure. Total plasma platinum, which represented free carboplatin, protein-bound platinum and metabolites, declined triexponentially; plasma half-lives (t1/2 lambda 1, 0.2 to 0.4 hr; t1/2 lambda 2, 1.3 to 1.7 hr; t1/2 lambda 3, 22 to 40 hr) and total body clearance (CLTB 2.8 +/- 0.5 L/m2/hr) were dose independent. Maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) increased proportionally with dose. Plasma ultrafilterable platinum and carboplatin concentrations at doses of 375 and 450 mg/m2 declined in a biphasic manner. Plasma carboplatin elimination (t1/2 lambda 1, 0.50 hr; t1/2 lambda 2, 2.2 hr) and CLTB (4.4 to 5.6 L/m2/hr) were also independent of dose; AUC and Cmax increased proportionally to dose. Plasma free platinum was essentially all carboplatin for 8 or 12 hours after administration. Carboplatin did not bind to plasma protein in vitro but did degrade (t1/2-26 hours) to yield a reactive intermediate that bound rapidly and irreversibly to protein. The long terminal elimination half-life of plasma platinum was associated with irreversible binding of a platinum metabonate to plasma protein. The urinary excretion of platinum (0 to 24 hours) accounted for 58 to 72% of doses in 12 to 24 hours. The remainder of the dose is slowly excreted. The pharmacokinetics, in vivo stability, protein binding, and elimination of carboplatin are distinct from the first-generation analog cisplatin.

A phase I study of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (PLAC) was conducted in 88 patients; 36 with solid tumors and 52 with hematological malignancies, using 2 different schedules. Schedule 1 employed a single oral administration and Schedule 2, 5-day consecutive daily oral administration. In Schedule 1, the daily dose was initiated with 1 mg kg-1 which was escalated up to 24 mg kg-1 according to the modified Fibonacci's method. Side effects included nausea, vomiting and skin rashes, but myelosuppression was not seen within this dose range. In Schedule 2, the daily dose was started with 1 mg kg-1 which was escalated up to 24 mg kg-1. Major side effects were nausea, vomiting and anorexia, and mild myelosuppression was noted at 12 mg kg-1 or more. The dose-limiting toxicity was gastrointestinal toxicity, which appeared at 3.3 mg kg-1 or more and became frequent at 7 mg kg-1 or more. Pharmacokinetic study revealed that the plasma concentrations of PLAC and ara-C, obtained by the oral intake of 3.3 mg kg-1 or more of PLAC, were sufficient for these compounds to exert cytotoxic effects on various human leukemia cells in vitro. Based on these observations and plausible mechanism of action of PLAC, further clinical study should be carried out in a treatment schedule of considerably prolonged administration period with 3.3-6 mg kg-1 day-1 of PLAC.

In an attempt to establish a better cancer chemotherapy, the metabolism of fluoropyrimidines was investigated in cancer patients.Both uridine phosphorylase (UrdPase) and thymidine phosphorylase (dThdPase) activity were estimated, using resected stomach or breast cancer specimens as mate rial. Autopsy specimens were also used to determine the whole body distribution of the enzymes in patients with gastric cancer.As a result, it was demonstrated that dThdPase activity was dominant compared to that of UrdPase. Accordingly, it was considered that 5-fluorouracil (FUra) wasmainly activated, via 5-fluoro-2-deoxyuridine (FdUrd), to produce 5-fluoro-2-deoxy - uridine 5-monophosphate (FdUMP), an active form of FUra. Further, it was also observed that both 1-(2-tetrahydrofurany1)-5-fluorouracil (FT) and 5'-deoxy-5-fluorouridine (5'-DFUR) were activated by dThdPase to form FUra. It was empha sized that this dThdPase activity was over 5-fold higher in tumor tissues than in nor-mal tissues. This observation would indicate that the compounds would exert a tumor-selective toxicity in cancer patients.

Contact B mode ultrasound was used to evaluate 53 patients with malignant lymphoma stages III and IV. The echographic characteristics of retroperitoneal involvement by these lesions were evaluated to establish diagnostic criteria. This method can be used also to evaluate regression of retroperitoneal tumor involvement of paravertebral or para-aortic lymph nodes during anticancer chemotherapy.

Magnification radiography was applied for the diagnosis of the biliary tract diseases including cancer. Our X-ray unit was consisting of HITACHI DR-155-23 U-6M-55P and 0.1 mm focal-spot tube, FFD 80 cm giving a magnification of x2 with the conditions of 60 kVp, 20 mA, 0.8 sec. Intensifying screens such as Kyokko LH II (for a standard sized subject) or DuPont Q II (for an obese subject) were used in combination with Fuji RX films. We confirmed a high diagnostic value in revealing early lesions of this sytem. The skin dose test indicated that this technique was routinely applicable with safety for clinical use.

Differential diagnosis of breast tumors was performed by a sensitivity graded method of two dimensional (B-scan) ultrasonotomography on 235 cases. The clinical significance of several new differential criteria such as tadpole-tail sign, lateral shadow sign, bilateral disappearance of distal wall echoes for benign lesions, acoustic middle shadow sign, and complete disappearance of distal limit of tumor echoes for malignant lesions, was evaluated in 67 histologically proven cases. Bio-acoustic mechanisms for the appearance of such differential points are discussed. Breast cancer was correctly diagnosed in 90% of the cases, the rate for small cancer (less than 2 cm) being 82%. Scirrhous carcinoma, papillary carcinoma, and medullary carcinoma were correctly diagnosed in 100%, 88%, and 81% of the cases respectively, whereas benign lesions such as fibro-cystic mastopathy, fibroadenoma, and cyst were correctly diagnosed in 100%, 83%, and 100% of the cases respectively.

N4-Palmitoyl-1-β-D-arabinofuranosylcytosine (PLAC) was administered PO to 76 patients with acute leukemia, myelodysplastic syndromes (MDSs), and myeloproliferative disorders (MPDs). Of 20 patients with acute myelogenous leukemia, 2 achieved complete remission, and the only patient with acute lymphoblastic leukemia achieved partial remission. Remission was reached with PLAC 100–300 mg/day 25–66 days after the start of therapy. Among 22 patients with MDS, 1 patient achieved a good response and 8 achieved partial response. Responses were reached with PLAC 50–200 mg/day 7–153 days (median, 33 days) after the start of therapy. Improvement of polycythemia was observed in all 5 patients with polycythemia vera, and reduction of thrombocytosis was observed in 5 out of 6 patients with essential thrombocythemia and myelofibrosis. An antileukemia effect was noted in 1 of 5 with chronic myelogenous leukemia. Major side effects were gastrointestinal toxicities and myelosupression. In spite of the disadvantages, such as unpredictable absorption and a lower response rate to acute leukemia compared with its parent compound, this antileukemia Ara-C analogue that is administrable PO will be useful in the treatment of MDSs and MPDs, which do not necessarily require admission to hospital, and in the treatment of acute leukemia of the aged, a condition for which intensive chemotherapy is not appropriate.

A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1 x 10(5) units/m2. The dose was escalated up to 16 x 10(5) units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16 x 10(5) units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12 x 10(5) units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5 x 10(5) units/m2.

Forty-five previously-untreated adult patients with acute myelogenous leukemia (AML) were treated with N4-behenoyl-1-β-D-arabinofuranosyl-cytosine (BHAC) in a multi-institutional cooperative study. Among 41 evaluable patients, 15 (36.6%) achieved complete remission (CR) and 10 (24.4%) achieved partial remission by daily administration of 3 to 8 mg/kg of BHAC. Higher daily doses (5 mg/kg or more) produced higher CR rates, and all of the CR were observed among the patients receiving a total BHAC dosage of 50 mg/kg or more in a period of 10 days or more. The side effects were mild and acceptable: nausea–anorexia was observed in 27% of the patients and vomiting in 17%. The results of this study thus indicate BHAC to be effective for remission induction of AML, and to deserve further clinical trials in combination with other anti-leukemic drugs. Cancer 56: 1913-1917, 1985.

Statistical and clinical studies were carried out in 1443 patients with tumors of reticuloendothelial system (RES) and 2188 patients with tumors of lymphoid tissue treated between 1953 and 1962 at universities and other hospitals in Japan. It is noteworthy that the incidence of lymphoid reticulum cell sarcoma is high in Japan. However, the incidence of tumors of RES and lymphoid tissue is still lower than that in most of other countries. As to the age distribution there was a significant difference between Japan and other countries, and it has been suggested that the incidence of lymphoid reticulum cell sarcoma in over 55 years of age was actually increasing. There were some differ-ences in frequency of initial symptom, presenting symptoms and signs between tumors of RES except lymphoid reticulum cell sarcoma and lymphoid tissue. The characteristic hematologic findings have not been observed at the initial phase of tumors of RES and lymphoid tissue. Also in this paper pathophysiology, effects of therapies and survival time of patients with tumors of RES and lymphoid tissue have been reported.

Effects of glucagon, prostaglandin El and dibutyryl cyclic 3', 5'-AMP upon the transmembrane action potential and the myocardial contractile force were investigated by using the isolated, perfused guinea pig heart by Langendorff's technique. The positive chronotropic and inotropic actions were observed by administering these agents into perfusion-cannula, and these effects were not blocked by propranolol. All of these agents produced shortening of the repolarization phase 2 (plateau phase) and increased the membrane resting potential in magnitude. The possible mechanisms underlying these changes is discussed in the light of cardiac cellular physiology and of the action of cyclic 3', 5'-AMP in the two messenger system.

(1) Autopsy data observed in the National Cancer Center Hospital in Japan were analyzed with reference to cardiac metastasis.(2) Between a period from 1962 to 1965, among 765 deaths from malignant neoplasm which did not include leukemia, over-all incidence of cardiac metastases was 9.7%.(3) Incidences of cardiac metastases in the patients with carcinoma of esophagus, carcinoma of stomach, carcinoma of rectum, carcinoma of lung, reticulum cell sarcoma, carcinoma of breast and carcinoma of tongue were 4.0%, 4.3%, 8.3%, 18.0%, 20.6%, 25.0% and 50.0%, respectively.(4) Number of cases with great vessels' involvement was 13 (1.7%).(5) Seven cases with direct invasion and 5 cases with disseminated pericardial metastases out of 28 cases with pericardial involvement were observed.(6) No effect of radiation therapy on either incidence or distribution of cardiac metastases was observed in all cases except cases with carcinoma of tongue.

The rate of suspended load in the open channel flow may be evaluated from integration on the product of concentration of suspended load and the velocity of the flow, at each point in the depth.In this paper the analytical evaluations of the rate of suspended load in the wide open channel is calculated by using beta function and sereis expansion. And an example of this evaluation using data of the Mississippi river by E. W. Lane and A. A. Kalinske is given.

Isoproterenol was infused intravenously into subjects with lung cancer, in a search for some useful parameters for evaluation of preoperative functional cardiac reserve. The hemodynamic responses to its infusion was noted to be different in patients with and without left ventricular hypertrophy, when the cardiac output, the stroke volume, the left ventricular work and the tension-time index were concerned. It appears that the inotropic and chronotropic actions of IPR are clearly intensified in the hypertrophied heart as compared with the normal heart. The possible mechanisms of this different response are discussed in the light of this study and a review of the literature.

1,3-Bis(tetrahydro-2-furanyl)-5-fluorouracil (FD-1) is a new masked compound of fluorinated pyrimidine and a derivative of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT-207). The pharmacokinetics of FD-1 and FT-207 were compared in the livers and kidneys of control mice and in mice (DD males) pretreated with phenobarbital. The half-time in the liver of FD-1 orally administered was about 40 minutes, whereas that of FT-207 in the liver was about 3 hours. Hepatic concentrations of 5-fluorouracil (FUra) originating from FD-1 were three to five times as much as those originating from FT-207. FD-1 formed 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-T-F-FU) and FT-207 by a ratio of about 3 to 10, respectively. Although FD-1 had a short period of half reduction, FT-207 and 3-T-F-FU had a half-time lasting for 3--4 hours. In contrast, the renal concentration of FD-1 was one-third that of FT-207. Oral administration of FD-1 to the mice pretreated with phenobarbital elevated the FT-207 and 3-T-F-FU levels in the livers to twice the levels in the control mice and further elevated the FUra levels in the livers to twice the levels in the controls. These results indicate that FD-1 is catabolized in the liver by microsomal enzymes (including cytochrome P450) faster than is FT-207, which consequently enlarges the hepatic pool of the intermediates on the way to FUra formation.

Studies were performed on the clinical basis of chemotherapy for human cancer with uracil and l-(2′-tetrahydrofuryl)-5-fluorouracil (FT). In 62 operated patients with stomach, breast, and uterine cancers, the concentration of 5FU and FT were compared in serum, tumor and normal tissues 1, 2, 4, 6, 8, and 12 hours following the administration of 300 mg of UFT (300 mg of FT plus 672 mg uracil, a uracil/FT molar ratio of 4), or FT alone. It was found that the level of 5-FU in tumor tissue remained above 0.05 mcg/g over 12 hours. This value for 5-FU corresponds to a minimum inhibitory concentration in thein Vitro experiment with L1210 cells. Blood levels of 5-FU increased up to 0.1 mcg/ml 1 hour after UFT administration and then decreased below 0.05 mcg/ml. The drug concentration in normal tissues was lower than that of the tumor tissues. On the basis of the above findings and phase I study, a protocol of UFT-therapy was made and applied for the treatment of gastric cancer. Our patients were given an oral dose of 300 mg of UFT twice a day per 50 kg body weight (12 mg/kg BW). Therapeutic effects were detectable in 7 of 20 cases. In addition, a combination of mitomycin C (6 mg i.v. weekly) with UFT seemed to improve the response rate (5/7). Diarrhea (15%) and skin pigmentation (10%) were major side effects of UFT.

1-β-D-Arabinofuranosylcytosine (ara-C) [7] is the mainstay of the treatment of acute myelogenous leukemia in adults [6]. It has, however, several drawbacks in that it has an extremely short half-life [11] and is very schedule-specific [17], which makes it less than ideal for clinical use. For this reason, attempts have been made to find other derivatives that might act as masked precursors, have long half-lives as well as less schedule dependency, give less toxicity, and perhaps achieve better clinical results [8, 10. 12. 13].

TANAKA, M. and KIMURA, K. Differential Sensitivity of Leukemic Cells to Growth Inhibition by Deoxyadenosine and Deoxycoformycin. Tohoku J. exp. Med., 1985, 147 (4), 331-341-Both established cell lines and human leukemic cells in circulating blood which were incubated in vitro with 2'-deoxyadenosine (AdR) plus adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), showed different metabolic responses depending upon the histologic and immunologic types of leukemia. The leukemic T-cell lines in tissue culture were 200-fold more sensitive than B-cell lines to the toxic effect of deoxyadenosine. The increased sensitivity of T-cell lines to AdR plus dCF was associated with the accumulation of deoxyadenosine triphosphate (dATP) in the cells. In established cell lines, an inversecorrelation was observed between ED 50 of AdR plus dCF and the relative increase of dATP levels in the cells after the incubation of the cells with AdR plus dCF. In circulating leukemic cells that had been incubated with AdR and dCF, dATP arose in all groups but the correlation was not found between the sensitivity of AdR and the relative dATP accumulation. The failure to find the correlation in patients's leukemic cells may be attributed to the heterogeneity of the response of the blasts to AdR and dCF.

Eighty-four previously treated adult patients with acute leukemia and malignant lymphoma were treated with (2"R)-4'-O-tetrahydropyranyladriamycin (THP). THP (10-55 mg/m2) was administered by i.v. bolus injection daily for acute leukemia, and according to three different schedules for malignant lymphoma: daily, weekly or once every 3-4 weeks. Complete and partial remission (CR and PR) were achieved by 1 (5%) and 3 of 19 patients with acute myelogenous leukemia and by 2 (13%) and 3 of 15 patients with acute lymphoblastic leukemia, respectively. All CRs were in the groups receiving 25 mg/m2 THP daily. CR and PR were achieved by 6 (14%) and 8 of 42 patients with non-Hodgkin lymphoma (NHL) and by 4 (50%) and 2 of 8 patients with Hodgkin's disease (HD), respectively. No particular sensitivity was found among the subtypes of NHL and HD. Response (CR + PR) was noted in 10 (40%) of 25 patients treated every 3-4 weeks, in 1 (17%) of 6 treated weekly, and in 9 (47%) of 19 treated daily. The major side effects were myelosuppression and gastrointestinal toxicities. Alopecia was observed in only 10 (12%) patients. ECG abnormalities were observed in 7 (10%) patients, all of whom had previously been treated with other anthracyclines. No severe cardiotoxicity was observed.

5-fluorouracil analogs investigated in this study include a combination of uracil and Ftorafur (UFT), Ethyl (+/-)-t-butoxy-5-fluoro-hexahydro-2, 4-dioxopyrimidine r-5-carboxylate (TAC-278), and 5'-deoxy-5-fluorouridine (5'-DFUR). In a total of 45 patients with gastric cancer, tumor tissue level of 5-fluorouracil (5-FU) was determined at 2, 4, 6, 8, and 12 hours following the oral administration of drug, using a resected stomach specimen as material. As a result, it was demonstrated that oral administration of 200 mg/m2 of UFT maintained above 0.05 microgram/g (minimum inhibitory concentration: MIC) of 5-FU in tumor tissues over 12 hours in 11 of 13 patients. On the contrary, 133 mg/m2 of TAC-278, and 200 mg/m2 or 300 mg/m2 of 5'-DFUR (which is activated by thymidine phosphorylase in man) did not produce an effective 5-FU concentration in tumor tissues. Serum 5-FU level was high in order of TAC-278, UFT, and 5'-DFUR. Clinical response rates obtained with UFT (200 mg/m2 twice a day), or TAC-278 (133-200 mg/m2, 3 times daily) were 27.5% (49 of 178 cases), and 8.3% (3 of 36 cases, by Koyama et al.), respectively. Fisher's direct probability test revealed that there was a significant difference (p less than 0.05) between them in the response rate. It was considered that the measurement of concentration of anticancer drugs in tumor tissues might provide us useful information for the designing of chemotherapy of gastric cancer.

The effect of immunotherapy with a protein-bound polysaccharide preparation termed PSK on remission duration and survival of adults with acute nonlymphocytic leukemia (ANLL) was studied in a prospective randomized cooperative trial. After having achieved complete remission and receiving a consolidation therapy, 73 patients were randomized either to maintenance chemotherapy or to maintenance chemotherapy plus immunotherapy with PSK. Ultimately 36 patients in the chemotherapy group and 31 in the chemoimmunotherapy group were evaluable. Six months after the last entry, immunotherapy with PSK showed a borderline beneficial effect on remission duration (P = 0.089) and on duration of survival (P = 0.062). When the data were analyzed 12, 18, and 24 months after the last entry there were no significant differences in duration of remission and survival between the two groups. However, analysis of the data of patients who had maintained complete remission for more than 270 days revealed that immunotherapy had a suggestive beneficial effect (P = 0.105), prolonging the 50% remission period by 418 days (885 vs 467 days). Thus, immunotherapy with PSK seems to be active in the treatment of adult ANLL when used for maintenance therapy in combination with chemotherapy, especially in patients with a good prognosis.