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Purpose: KRN8602 (3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 · HCl) is a newly developed anthracycline that has been found to be effective against multidrug-resistant tumor cells in vitro and in vivo. In order to clinically confirm these promising preclinical observations, we performed a phase II trial of KRN8602 in patients with anthracycline-resistant metastatic breast cancer. Methods: Of 41 patients registered with metastatic breast cancer, 37 were eligible and were given at least two cycles of KRN8602 15 mg/m2 per day at 3–4 week intervals by intravenous bolus injection on days 1, 2, and 3. Results: Of the 37 patients, 6 (16.2%, with a 95% confidence interval of 4.3–28.1%) had a partial response (PR). No complete responses (CRs) were observed. The difference between response rates according to prior history of anthracycline administration was not significant. Myelosuppression was moderately severe, with grade 3 or 4 leukopenia occurring in 65%. Severe nausea/vomiting was observed in 44% of the patients. Conclusions: The results indicate that KRN8602 has modest activity in refractory metastatic breast cancer and is associated with relatively severe toxicity. Furthermore, the preclinical finding that KRN8602 overcomes anthracycline resistance was not reliably reproduced in this clinical phase II trial.

The second 5-year study of postoperative adjuvant therapy in patients with breast cancer between 1985 and 1988 was performed by the Study Group for Adjuvant Chemoendocrine Therapy for Breast Canecr (ACETBC). This report describes the results of a meta-analysis of the outcome. A total of 3012 patients with stage II, estrogen-receptor-positive primary breast cancer who underwent radical surgery (total mastectomy with at least axillary dissection) were eligible for the analyses. On the day of surgery, all patients received 13 mg/m(2) of mitomycin C (MMC) intravenously. Patients were then given one of two adjuvant chemoendocrine therapies for 2 years:regimen A, consisting of tamoxifen citrate (TAM) 30 mg/day, or regimen B, consisting of TAM 30 mg/day plus tegafur (Futraful, FT)600 mg/day. The results from all eligible patients were included in a meta-analysis according to the method of Peto et al. The odds reduction rate was 12 +/-13% (log-rank test, P= 0.35)for the 5-year survival rate and 16 +/- 10% (log-rank test, P=0.093)for the 5-year non-recurrence rate. In terms of the 5-year non-recurrence rate. regimen B(with FT)yielded slightly, but not significantly, better results than regimen A. In addition, stratified analyses were carried out with respect to the 5-year non-recurrence rate. Regimen B(with FT)yielded significantly better results than regimen A in patients with four or more positive axillary nodes (log-rank test, P= 0.039) and yielded slightly, but not significantly, better results than regimen A in premenopausal patients (log-rank test, P= 0.079).

The effects of medroxyprogesterone acetate (MPA) therapy on advanced or recurrent breast cancer and its influence on blood coagulation and the fibrinolytic system were compared among three different therapy regimens consisting of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) + MPA and CAF or MPA alone. A clinical response was observed in 42.9% (9/21) of the patients for CAF + MPA, 36.4% (8/22) for CAF and 23.8% (5/21) for MPA alone. No marked thrombosis or its prodromal condition was observed in any group. The effects on the test values for blood coagulation and the fibrinolytic system did not significantly change in the CAF group. However, both AT-III and protein C significantly increased above the normal ranges in the CAF+MPA and MPA groups. Increases in factor X, plasminogen, and alpha 2-plasmin inhibitor/plasmin complex (PIC) and decreases in fibrinogen, tissue plasminogen activator, and D-dimer, were all observed in the MPA and CAF + MPA groups, especially in the MPA group, although these changes remained within the normal ranges. The data indicated that MPA has various influences on blood coagulation and the fibrinolytic system, but these changes did not suggest activation of the blood coagulation system.

リコンビナント・ヒト.エリスロポエチン (r-HuEPO) を消化器癌を中心とする一般外科手術例に2001U/kg術前7日間, 術後14日間連日投与し周術期輪血量節減への有用性を検討した.1.術前投与で末梢血ヘモグロビン濃度, ヘマトクリット値, 赤血球数は有意に上昇した.2.r-HuEPO投与により術後貧血は第4病日以後順調に回復し, 対照群に比べその回復は有意に良好であった.3.副作用としては感冒様症状, 肝機能障害, 発熱, および発疹が各1例 (5.9%) に認められたが重篤なものはなかった.他の92.2%では副作用や臨床検査値異常は認められず, r-HuEPOは周術期にも安全に投与出来るものと思われた.以上より, 一般外科領域でもr-HuEPO投与は術前, 術後の貧血改善に有効であり, その適切な応用により周術期輸血の節減が可能と考えられた.

Experimental chemotherapy with 5-fluorouracil (5-FU; 60 mg/kg), 1-hexylcarbamoyl-5-fluorouracil (HCFU; 70 mg/kg), 3-(3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl)-1-ethoxym ethyl-5- fluorouracil (BOF-A2; 30 mg/kg) and UFT (20 mg/kg as tegafur with uracil at a molar ratio of 1:4) was performed using human gastric (H-111) and colon (Co-4) carcinoma strains in nude mice. 5-FU was administered ip with a q4d x 3 schedule and the other agents were given po daily for three weeks. Concentrations of 5-FU in the serum and the tumor were assessed by gas chromatography-mass fragmentography, two hours or 12 days (5-FU) after the last treatment, and thymidylate synthetase (TS) was assayed according to the method of Spears et al. using the same schedule. The antitumor activity of the agents was assessed in terms of the actual tumor weight at the end of the experiment. HCFU was effective against both strains and 5-FU was effective against Co-4, although the other agents were ineffective against either strain. Statistically significant correlations were found between the serum and tumor concentrations of 5-FU and antitumor activity. Statistically significant correlations were also observed between the antitumor activity and TS inhibition rate (TSIR) and the activity of free thymidylate synthetase (TSfree), with higher TSIR and lower TSfree resulting in higher antitumor activity. Therefore, TSIR and TSfree were thought to be promising indicators for predicting the antitumor activity of fluoropyrimidines.

大腸癌治癒切除におけるmitomycin C (MMC), 5-fluorouracil (5-FU), tegafur (FT)を用いた補助化学療法の有用性を検討するために,封筒法による無作為比較対象研究(1979年12月～1983年8,月)を行った.結腸癌と直腸癌に分け,結腸癌ではA群(MMC 50mg術中腸管内投与+FT 1年間投与),B群(5-FU 1,500mg術中腸管内投与+FT 1年間投与)の2群を比較し,直腸癌ではA群(MMC 10～4mg/body/回間歌投与+FT 1年間投与),B群(5-FU 250mg/body/day術後2週間連日投与+FT 1年間投与)の2群を比較した.集積症例は378例(結腸癌171例,直腸癌207例)であった.5年生存率および健存率では,結腸癌A,B群問に差は認められなかったが,直腸癌ではA群に比しB群に予後良好な傾向を認め,特に直腸癌DukesC症例においては有意差(生存率p=0.047,健存率p=0.013)を認めた.

Droloxifene, a new tamoxifen (TAM)-derived compound, has excellent antiestrogenic activity. This compound exhibits less endogenously estrogenic but higher antiestrogenic activity, with better tolerability than TAM in experimental models. Two phase II studies of droloxifene were performed in 47 Japanese institutions to assess the optimal dose. The first was a randomized comparative study using 20, 40, and 80 mg, respectively, once a day. The other was a pilot study using 120 mg once a day. The subjects of both studies were women with primary or recurrent advanced breast cancer, regardless of estrogen receptor status and menopausal status. Of 94 patients enrolled in the comparative study, 22, 26, and 23 were evaluable in the 20-, 40-, and 80-mg groups, respectively. Of the 71 evaluable patients, 14 (19.7%) were negative for estrogen receptor, and 36 (50.7%) had a previous history of TAM therapy. The response rate complete response + partial response (CR + PR) was 13.6% for 20 mg, 15.4% for 40 mg, and 17.4% for 80 mg. The rate of no change (NC) was 31.9%, 46.1%, and 47.8%, and that of progressive disease (PD) was 54.5%, 38.5% and 34.8%, respectively, in the 20-, 40-, and 80-mg groups. In the other study, 16 patients were enrolled in the pilot study with 120 mg of droloxifene, of whom 14 were evaluable. The response rate was slightly higher: four responders (28.6%) were assessed as CR + PR, six (42.9%) as NC, and four (28.6%) as PD. These results suggest that the response rate may be dose-dependent and that PD rates seem lower in the higher doses. No serious side effects were encountered, and droloxifene was well tolerated even in the higher doses. At present, a final randomized dose-finding study with 80 mg/day and 120 mg/day is being carried out.

Resectability rate of the aged patients (≥ age of 72) with cancer of the thoracic esophagus in recent ten years (1980-89) increased to 70.5%, as compared with resectability in former ten years (1970-79) of 51.5%. This increase of resectability was attributable to the improvement of the perioperative management such as cardiorespiratory and nutritional supports. Assessing the operability of the aged patients, physiological age, which is based on the reserve function of the vital organ such as heart, lung, liver and kidney, rather than calendar age should be considered.As a surgical strategy for the aged patients with cancer of the thoracic esophagus, who are assessed not to be indicated to the standard thoracotomy and laparotomy, transhiatal esophagectomy without thoracotomy is useful, even if palliative surgery. Based on this strategy, eight aged cases underwent transhiatal esophagectomy without thoracotomy, and three cases survived more than three years.There is no significant difference of long term survival between the aged patients and over all cases.

Although brainstem infarction is known to cause cardiopulmonary arrest, there are only a few reported cases. We experienced a patient who was brought into our emergency department with cardiopulmonary arrest. After successful resuscitation, she remained comatose, her eyes being fixed in the middle position with no light reflex. She was quadriplegic, but showed occasional right-sided myoclonic involuntary movement. Brain computed tomography performed on the fourth hospital day revealed a diffuse low-density area in the left temporo-occipital lobe. Secondary brainstem infarction due to cerebral hypoperfusion or hypoxemia was ruled out, as other causes of cardiopulmonary arrest were not found. We considered that her cardiopulmonary arrest was caused by brainstem infarction. Cardiopulmonary arrest due to brainstem infarction may be overlooked because of diagnostic difficulty.

The efficacy and toxicity of (2''R)-4'-O-tetrahydropyranyl adriamycin (THP) were assessed in the treatment of patients with advanced breast cancer by the Japan THP Study Group. Mean plasma levels of THP after single-dose administration revealed triexponential decay characterized by an initial half-life of 0.89 h. A higher concentration of THP was obtained in the metastatic lymph nodes than in the breast cancer tissue at 4 h after administration (4.01 vs. 1.17 micrograms/g). Whereas 1 complete (CR) and 12 partial response (PR) were observed in 56 evaluable patients after administration of THP alone (23.2%), 1 CR and 12 PR were observed in 37 evaluable patients who had combination therapy including THP (35.1%). Multivariate analysis of prognostic factor revealed that the site of metastases had the most valuable prognostic significance; second was irradiation in the previous treatment, and third was the disease-free interval. Life-table analysis adjusted with the Cox proportional hazard model revealed a similar survival curve of patients receiving THP-cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) to that of those receiving CAF only in spite of the low incidence of toxicity in the THP therapy.

The antitumor activity and pharmacokinetics of (7R, 8S, 10S)-10-((3-deamino- 3-(4-morpholino)-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-8- ethyl- 7,8,9,10-tetrahydro-1,6,7,8,11-pentahydroxy-5,12-naphthacenedione hydrochloride (KRN8602) were evaluated using five human breast carcinoma xenografts in nude mice. The maximum non-toxic dose of KRN8602 was 2 mg/kg by q4d x 3 intraperitoneal and peroral administration. KRN8602 showed significant antitumor activity against MX-1, which is less sensitive to adriamycin, with the chemotherapeutic indices of 13.0 for po administration and 9.5 for ip injection. Although KRN8602 also inhibited the growth of T-61 significantly, the antitumor activity of this agent against the other three breast carcinoma xenografts was limited. To elucidate this discrepancy, pharmacokinetic analysis and MTT assay were conducted using the KRN8602-sensitive MX-1 and KRN8602-insensitive R-27. While no differences were observed in the area under the curve and the peak concentration of KRN8602 for each tumor, a difference in the sensitivity of the tumor strains was obvious in MTT assay. The efficacy of this agent seemed to depend on the sensitivity of each type of tumor cell rather than the concentration of agent in tumor tissues. If it were possible to select patients with sensitive tumor cells to this agent by the MTT assay, the phase II trial might be completed within a short period by reducing the number of studied patients.

The ability of the host-immune defense mechanism of nude mice and their immunocompetent littermates to prevent liver metastases from the murine colon carcinoma, colon-26, was assessed. Give thousand tumor cells suspended in 0.05 ml of Hank's balanced salt solution were inoculated into the spleens of BALB/c nu/+ and BALB/c nu/nu mice. On the 21st day after inoculation, all the mice were sacrificed, and the liver metastases counted and the livers weighed. All the BALB/c nu/+ mice were found to have developed hepatic metastases with a mean of 10 nodules, whereas no hepatic metastases were observed in any of the 10 BALB/c nude mice. On the other hand, 4 of 6 nude mice developed hepatic metastases after treatment with anti-asialo GM1 antibody. These results indicate that the BALB/c nude mouse has an excellent host-immune defense mechanism for preventing liver metastasis, with NK cells in the liver and/or blood circulation perhaps playing an important role.

過去12年間に経験した原発性大腸癌944例のうちイレウス症状を呈した87例 (9.2%) を非イレウス症例と臨床的および病理学的に対比検討した.イレウス症例はDukes C, Dの進行例が多く, 治癒切除率は59%にとどまった.治癒切除例の5年生存率は結腸64%, 直腸38%で, いずれも非イレウス症例より不良であった, 右側大腸癌イレウス症例の68%は待期手術が施行され, 緊急手術例のほとんどで一期的切除吻合が行われた.一方左側大腸癌イレウス症例の85%には緊急手術が施行され, その69%で一時的人工肛門造設に続く段階的切除が行われた.緊急に一期的切除を施行した症例ではリンパ節郭清の程度が低かったのに対して, 段階的切除例ではリンパ節郭清が不十分であったために非治癒切除となった症例はなく, 治癒切除率も段階的切除例で一期的切除例よりも高かったことより, 左側大腸癌イレウスに対する治療として段階的切除は妥当であると考えられた.

We have reported that temperature-sensitive liposomes containing adriamycin (TS-Lip-ADM) mainly delivered ADM to heated tumors with local hyperthermia and enhanced antitumor effect. TS-Lip-ADM composed of DPPC (Tc= 41°C) (type-I) released considerable amount of ADM in the blood stream, making its clinical application difficult. To raise the stability of the liposomes, we included various ratio of DSPC (Tc = 54°C) and/or cholesterol (Chol) in the liposomal membrane and assessed temperature sensitivity. Addition of DSPC reduced ADM leakage from the liposomes at lower than 40°C and raised the maximal releasing temperature. Chol makes liposomes more stable in the presence of serum. TS-Lip-ADM including Chol up to 20 mol% remained temperature-sensitive. Inclusion of 30 mol% Chol abolished this characteristic. We made TS-Lip-ADM composed of DPPC, DSPC and Chol, in the molar ratio 7 : 1 : 2 (type-II), and investigated the selective delivery of ADM from type-II to NUE human hepatoma cells inoculated in nude mice and antitumor effect evaluated by the tumor weights, compared with type-I. NUE tumor uptake of ADM was increased by local hyperthermia at 42 °C for 30 min. ADM concentration in heated type-II tumors was about three times as high as in heated free ADM tumors, but not different from type-I significantly. Hyperthrarmia enhanced the antitumor effect.

Recent studies have demonstrated that tegafur-uracil (UFT) is useful for the adjuvant treatment of various types of cancers. To determine whether nucleoside metabolizing enzymes could be used to predict the response to UFT treatment in women with primary breast cancer, we retrospectively analyzed archived tumor tissue samples obtained from the 3rd Adjuvant Chemo-Endocrine Therapy for Breast Cancer (ACETBC) study, in which adjuvant treatment with tamoxifen (TAM) plus UFT for 2 years was compared with TAM alone for 2 years. Samples of tumor tissue were obtained from 192 premenopausal women with node-positive invasive breast cancer. The tissue samples were examined immunohistochemically to study the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), as well as the expression of Her2 and p53. In patients with TS-positive tumors, the risk of relapse was significantly lower in the tamoxifen plus UFT group than in the tamoxifen alone group. After 2 years, however, there was a trend towards a decrease in the relative predictive value (RPV) of TS with time. No relationship to outcome was detected for TP or DPD. Expression of Her2 or p53 was a significant prognostic indicator in the tamoxifen alone group. TS, but not TP or DPD, may be a useful predictor of response to UFT therapy. After 2 years, the RPV of TS decreased with time, suggesting that 2 years of treatment with oral fluorouracil derivatives may be inadequate. Further studies are required to investigate this possibility.

Goserelin (GOS) therapy in an adjuvant setting for estrogen receptor(ER)-positive premenopausal patients with breast cancer was assessed in a randomised comparative study.ER positive premenopausal patients with n + or n 0 and Tor = 3 cm received tamoxifen (TAM) 20 mg/day, GOS 3.6 mg/4 weeks or GOS + TAM for 2 years, and the clinical efficacy and safety of these regimens were assessed.In the data analysis of total 207 patients, hazard ratios of disease free survival (DFS) and overall survival (OS) in the GOS group compared to the TAM group were 0.87 and 2.10,respectively. The incidence of adverse drug reactions was similar (42-55%) in all three groups. Since the number of patients in this study did not reach the target number, the efficacy could not be assessed from a statistical aspect. Therefore,meta-analysis with similar foreign studies(ZIPP) was implemented. The results of meta-analysis showed that the hazard ratios of DFS and OS in the GOS group compared to the non-GOS group were 0.83 and 0.85, respectively.Although the analysis of 207 patients did not show any statistically significant difference between each of the treatment groups, the results of meta-analysis showed a significant prolongation of DFS in the GOS group. Also high tolerability of GOS was suggested. From these results, GOS was considered highly useful in adjuvant therapy for ER-positive premenopausal patients with breast cancer.

Purpose This article reports the results of a pooled analysis of six randomized trials conducted to study the efficacy of uracil and tegafur (UFT) in the adjuvant treatment of node-negative breast cancer patients. Patients and Methods Six randomized controlled trials on node-negative breast cancer patients were conducted from 1992 through 1995 in Japan that included the three, three-arm trials (control [no adjuvant], UFT, and tamoxifen [TAM] groups) and the three, four-arm trials (control, UFT, TAM, and UFT plus TAM groups). Pooled analysis was performed on the data obtained from these six trials (involving 2,934 patients). Results Overall survival was compared between the UFT group (including both the UFT group and the TAM plus UFT group) and the non-UFT group (control group and TAM group). A significant difference (P = .04) was observed in 5-year survival rates between the UFT (95.9%) and the non-UFT (94.0%) groups. Overall survival was also compared between the TAM group (TAM group and TAM plus UFT group) and the non-TAM group (control group plus UFT group). The 5-year survival rate (95.2%) in the TAM group was not significantly different from that (93.9%) in the non-TAM group, but the subset analysis showed a significant (P = .01) improvement in the estrogen receptor-positive subset. Conclusion Adjuvant UFT improves the overall survival of node-negative breast cancer patients. Given that UFT has milder adverse effects, it is suggested that UFT can be a useful alternative to doxorubicin and cyclophosphamide, or cyclophosphamide, methotrexate, and fluorouracil in the adjuvant treatment for node-negative breast cancer.

Purpose: We compared the therapeutic usefulness of doxifluridine (5′-DFUR) alone and a combination of 5′-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. Patients and Methods: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5′-DFUR alone or 5′-DFUR plus CPM. All patients initially received 5′-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5′-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5′-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5′-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. Results: Of the 1,088 eligible women, 546 were assigned to receive 5′-DFUR alone and 542 were assigned to receive 5′-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5′-DFUR plus CPM than in those who received 5′-DFUR alone (log-rank test, P = .021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5′-DFUR group and 32.3% of patients (175 of 542) in the 5′-DFUR plus CPM group (χ2 test, P < .001). Conclusion: Combination therapy with 5′-DFUR plus CPM is more effective in preventing recurrence than 5′-DFUR alone.

Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 ± 17% (p = 0.33) and 21 ± 11% (p = 0.060), respectively. Multivariate analysis using Cox’s proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 ± 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 ± 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I – IIIA breast cancer for the prolongation of the reccurence-free survival period.

To assess the efficacy of 5'-DFUR, an intermediate of capecitabine, for adjuvant treatment of early breast cancer, we conducted an open-labeled multi-center randomized controlled trial to compare postoperative 5'-DFUR treatment with surgery alone. We enrolled 1217 primary breast cancer patients and randomly assigned them into two treatment groups; one received six-month postoperative 5'-DFUR treatment by consecutive or intermittent administration, and the other surgery alone. Follow-up surveys were conducted once a year for all subjects simultaneously and examined their outcome/presence or absence of the cancer recurrence. The central study committee reviewed all follow-up data and judged the recurrence data to be used for the analysis. Eight-year follow-up data showed no significant differences in relapse-free and overall survival between the two groups, and 5'-DFUR treatment regimen showed an extremely high tolerance. Possible explanations are discussed for the finding of no significant survival difference between adjuvant 6-month 5'-DFUR monotherapy and surgery alone in early breast cancer.

A randomized controlled comparative study of oral medroxyprogesterone acetate (MPA) 1,200 mg (arm I) and 600 mg (arm II) was conducted in 80 patients with advanced or recurrent breast cancer. There were no significant differences between arm I and arm II in terms of response rate, duration of response and survival, or in terms of incidence and severity of adverse reactions. The lowest serum MPA concentration in responders tended to be higher than that in nonresponders. In the cohort of this study, the lowest concentration in partial response was 17.4 ng/ml, suggesting that this level may be the required minimum serum concentration.

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located throughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage IIIa breast cancer. Patients with estrogen receptor-positive [ER( + )] breast cancer were treated with two types of regimens, ie, cyclophosphamide + adriamycin + fluorouracil (CAF; 2 cycles) + Futraful (FT) or CAF (2 cycles) + FT + tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER( + ) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation. The 5-year survival rate was 77.2% for the CAF + FT group and 74.6% for the CAF + FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF + FT + TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF + FT + TAM group was significantly higher than that for the corresponding patients in the CAF + FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF + FT+TAM group than in the CAF + FT group). Patients with estrogen receptor-negative [ER( -)] breast cancer were treated with two types of regimens, ie, CAF + FT or CAF + FT + adriamycin (ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478 (93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF + FT group and 63.0% for the CAF + FT + ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF + FT and CAF + FT + ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF + FT+ADR group than in the CAF + FT group.

Using a cohort of macroscopic curative resections of gastric cancer at stages II, III, and IV, a randomized controlled trial was performed to elucidate the dose efficacy of intensive adjuvant cancer chemotherapy with mitomycin C. Between June 1983 and December 1986, 336 patients with gastric cancer from 31 institutes were enrolled in the study. The cohort was stratified randomly by the telephone method into two arms. Group A received 20 mg and 10 mg of mitomycin C per body intravenously (IV) on postoperative days 0 and 1, respectively, and then tegafur at 600 mg/body daily perorally (PO) from postoperative week 2 for 1 year. Group B also received 0.2 mg of mitomycin C per kg IV at 3, 6, 9, and 12 months after surgery. The background factors in groups A and B were essentially identical, and the adverse effects were tolerable in both groups. The total administered doses of mitomycin C were significantly higher in group B than in group A, according to the protocol. Although no significant differences were observed in the actuarial overall survival rates between groups A and B at stages II, III, and IV, favorable survival was observed in group B, which received histologically absolute curative resection. This dose-intensive adjuvant cancer chemotherapy would be useful for gastric cancer patients treated by histologically curative surgery. © 1994 Wiley-Liss, Inc.

The first collaborative studies of postoperative adjuvant chemoendocrine therapy for breast cancer (ACETBC) were carried out in 6 regions of Japan from 1982 to 1985, and the results were subjected to meta-analysis. Subjects consisted of Stage II and IIIa cases who underwent radical mastectomy with Brt + Ax or more extensive resection for primary breast cancer. Regimen A consisted of tegafur (Futraful: FT) alone at 600 mg/day, and regimen B of FT at 600 mg/day with tamoxifen (TAM) at 20 mg/day. The duration of the treatment was one year in the Tohoku and Kinki regions, and 2 years in the other 4 regions. Meta-analysis by Peto’s method showed an odds reduction of 20 ± 7% (logrank test:P = 0.0069) for the 5-year overall survival rate in 4740 eligible patients, and 25 ± 6% (logrank test: P>0.0001) for the 5-year disease-free survival rate. The odds reductions were both statistically significant, indicating that the adjuvant chemoendocrine therapy was effective. Subset analysis of data on 5 - year disease-free survival showed that FT plus TAM therapy was better in ER-positive and postmenopausal patients, whether axillary lymph nodes were positive or negative.

The usefulness of CAF [cyclophosphamide (CPA)/doxorubicin (ADR)/5-fluorouracil (5-FU)] + medroxyprogesterone acetate (MPA) therapy for advanced/recurrent breast cancer was studied in a randomised trial at 56 institutions. Patients received CAF therapy [CPA: 100 mg, orally, days 1-14; ADR: 30 mg/m2, intravenously (i.v.), days 1 and 8; 5-FU: 500 mg/m2, i.v., days 1 and 8) in arm I, or CAF + MPA therapy (CAF + MPA 1200 mg, daily) in arm II. The response rate was significantly higher (P = 0.041) in arm II (53.5%, 46/86) than arm I (36.6%, 30/82). The response rate by tumour site was significantly higher for lymph node and bone lesions in arm II. Partial response duration and overall response duration were significantly longer in arm II. Incidences of anorexia and nausea/vomiting were significantly higher in arm I but in arm II, moon face, oedema and vaginal bleeding were significantly higher. Many patients in arm II demonstrated improvement in performance status and weight loss, suggesting a beneficial effect of MPA. The chemoendocrine therapy with CAF + MPA appears to be more beneficial than CAF alone in the treatment of advanced/recurrent breast cancer.

We performed a preliminary phase II clinical trial of MX2; 3'-deamino-3'-morpholino-13-deoxy-10-hydroxycarminomycin (KRN8602) in patients with metastatic breast cancer who had failed to respond to previous chemotherapeutic regimens after clinical evidence of systemic disease. Twelve patients at a single institute received KRN8602 at a dose of 35 mg/m2 intravenously once every three weeks. All the patients were followed-up until their disease progressed. There was one complete response lasting 17 weeks and one partial response lasting eight weeks. Among the 12 patients, World Health Organization (WHO) grades 3 and 4 neutropenia were observed in five and two patients, respectively. Grade 3 anemia was observed in three patients but severe thrombocytopenia was not observed. Grade 3 nausea/vomiting was observed in eight patients. Alopecia was not observed. The results of this preliminary phase II trial suggest a need for further testing of the anti-tumor activity of KRN8602 in patients with metastatic breast cancer.

The effect of endothelin (ET)-1 on the adipogenic differentiation of 3T3-L1 preadipocytes was examined. Cellular morphology and lipoprotein lipase activity were used as differentiation markers. ET-1 inhibited the hormone-induced adipogenic differentiation of 3T3-L1 preadipocytes morphologically and biochemically in a dose-dependent manner. These findings promote ET-1 as a potent inhibitor of adipogenic differentiation, playing an important role in cellular differentiation of preadipocytes and making it a significant regulator of lipid metabolism.

A Phase I study of the new antiestrogenic drug toremifene was carried out in 27 Japanese women, using oral doses of 10–480 mg per day for one or five days. Serum concentrations reached a dose-dependent maximum 2–6 hours after each oral administration. Side effects were generally mild.

Adriamycin (ADM) entrapped in liposomes (Lip-ADM) was prepared and its therapeutic effects studied using the mouse leukemia cell line, P388, which metastasized to axillary lymph nodes after inoculation into the foot pads of CDF1 mice. Lip-ADM injections (7.5 mg/kg) were given into the foot pad at two-day intervals. Two series of experiments were performed; one in which Lip-ADM was administered on days 1,3 and 5 following tumor inoculation, and the other in which it was administered on days 5 and 7. Both Lip-ADM injection regimens significantly inhibited metastases to the lymph nodes as compared with mice given injection of saline solution. Furthermore, the therapeutic effects of three Lip-ADM injections were significantly greater than the effects of free ADM. Histological examinations of lymph nodes revealed that three injections of Lip-ADM completely eliminated tumor cells, whereas viable tumor cells were still observed in the lymph nodes after treatment with free ADM. The results of this study suggest that Lip-ADM is useful for the treatment of lymph nodes metastases and that the local injection of Lip-ADM, through such means as endoscopy, would be recommended as a clinical mode of application.

To define the relationship between atrial natriuretic polypeptide and the physiological changes of water and electrolytes after burns, the changes in plasma hormonal levels, including atrial natriuretic polypeptide, and urinary water and sodium excretions were examined in burned rats. Further, to elucidate the physiological significance of atrial natriuretic polypeptide after burns, the effects of a specific antiserum against atrial natriuretic polypeptide were determined in burned rats. Plasma atrial natriuretic polypeptide levels in rats following 30 per cent BSA full skin thickness burns were elevated for sustained periods (432.3 +/- 156.5 pg/ml, P less than 0.01 on day 1 postburn, 244.5 +/- 73.7 pg/ml, P less than 0.05 on day 3 postburn). Urine volume and sodium excretion decreased significantly during the first 72 h after burns. On day 3 postburn, urine volume and sodium excretion began to increase significantly. Specific rabbit antiserum against atrial natriuretic polypeptide was injected into the burned rats during this diuretic phase. Significant inhibition of diuresis and natriuresis was observed after the injection of antiserum (27.5 +/- 2.4 per cen decrease in urine volume, 57.1 +/- 10.4 per cent decrease in sodium excretion). These results suggest that atrial natriuretic polypeptide plays a physiological role in the regulation of urinary water and sodium excretion after burns.

The effect of pulmonary injury induced by aspiration of HCl on plasma atrial natriuretic polypeptide (ANP) level was examined in rats given a constant infusion of water and electrolytes. In addition, using specific antiserum against ANP, we investigated the physiological role of ANP in rats after HCl aspiration. Rats were housed individually in metabolic cages and were given a constant infusion of sodium solution via catheters chronically inserted into the jugular vein. Plasma ANP levels were elevated at 3 and 24 h after tracheal injection of 0.2 ml of 0.1 N HCl via the cricothyroid membrane. Urine volume and urinary sodium excretion increased during the first 24 h after acid aspiration. However, this increase was reduced by the injection of anti-ANP serum. Furthermore, the injection of anti-ANP serum resulted in a significant (P less than 0.05) increase in wet lung weight from a value of 0.74 +/- 0.06 (HCl aspiration with normal rabbit serum injection) to 0.83 +/- 0.07% of body weight. These results indicate that ANP plays a physiological role in the regulation of urinary water and sodium excretion after pulmonary acid injury and suggest that ANP elevated in plasma after pulmonary injury may prevent pulmonary edema with its diuretic action and/or some direct action on water movement in the lung.

In order to evaluate the efficacy of combined immunochemotherapy with mitomycin-C, tegafur, PSK and/or OK-432 as an adjunct for curatively resected gastric cancer, a prospective randomized controlled study using the envelope method was performed, in which 266 institutions from around Japan participated. The 3 year survival rates for all cases, and for ps(+)·n(+) cases, were insignificantly higher in the immunochemotherapy groups receiving PSK and/or OK-432 than in the control group. However, because 28.2 per cent of the cases were excluded from the final statistical analyses, the results of this study may have questionable statistical credibility. Changes in the stimulation index (SI) suggest that the administration of PSK may result in an inhibition of the immunosuppressive activity of cancer patients. The high SI group showed a significantly higher 4 year survival rate than the low SI group.

We examined the effect of chemotherapeutic agents on the estrogen receptors (ER) of breast carcinomas in vivo using human breast carcinoma strains (Br-10, T-61) serially transplanted into nude mice. When the tumor size reached approximately 1 X 1 X 1 cm, mitomycin C (MMC) at doses of 1, 2 and 4.5 mg/kg and cyclophosphamide (CPA) at a dose of 120 mg/kg, were administered once intraperitoneally, and the ERs of the tumors were measured sequentially by the dextran-coated charcoal method. Four days after the MMC administration at above doses, the binding sites of ER in Br-10 were not reduced and binding affinity was not affected. When the changes in ER content with time after the treatment with 4.5 mg/kg MMC and 120 mg/kg CPA were investigated, the ER content was found to be stable until 4 days after the treatment with both drugs, although the growth of T-61 had been significantly inhibited by the drugs. From these findings, it seems reasonable to initiate chemotherapy before endocrine therapy, since the chemotherapeutic agents did not reduce the ER content of the breast cancer strains.