Comparison of quantitative structure-activity relationship model performances on carboquinone derivatives.

Quantitative structure-activity relationship (qSAR) models are used to understand how the structure and activity of chemical compounds relate. In the present study, 37 carboquinone derivatives were evaluated and two different qSAR models were developed using members of the Molecular Descriptors Family (MDF) and the Molecular Descriptors Family on Vertices (MDFV). The usual parameters of regression models and the following estimators were defined and calculated in order to analyze the validity and to compare the models: Akaike's information criteria (three parameters), Schwarz (or Bayesian) information criterion, Amemiya prediction criterion, Hannan-Quinn criterion, Kubinyi function, Steiger's Z test, and Akaike's weights. The MDF and MDFV models proved to have the same estimation ability of the goodness-of-fit according to Steiger's Z test. The MDFV model proved to be the best model for the considered carboquinone derivatives according to the defined information and prediction criteria, Kubinyi function, and Akaike's weights.

Increased therapeutic efficacy of intra-arterial carboquone chemotherapy on a limb tumor in rats, by using an acidic vehicle adjusted with lactate.

We previously reported that the cytotoxicity of carboquone (CQ) was potentiated in vitro and in vivo under acidic conditions. In this study, an acidic vehicle adjusted with lactate at various low pHs was used for CQ intra-arterial (i.a.) injection, in order to enhance the antitumor effects of i.a. CQ chemotherapy. Treatments were evaluated in Wistar/KA rats bearing a limb tumor 5 days after the inoculation of 3 x 10(6) syngeneic RBT-1 tumor cells into the hind limb. In chemotherapy experiments using an intrafemoral injection of CQ at 1.5 mg/kg in phosphate-buffered saline (PBS, pH 7.4) or in an acidic vehicle at pH 5.0 or 6.0, the antitumor effects seen in rats given CQ in acidic vehicles, evaluated by tumor weight 14 days after treatment, were significantly greater than that seen in rats given CQ in PBS. There were no significant differences either in changes of body weight or in the number of leukocytes after treatment between the groups given CQ in PBS and in an acidic vehicle at pH 6.0. Although in the group given CQ at 2.0 mg/kg in PBS, the antitumor effect was the same as that observed in rats given CQ at 1.5 mg/kg in an acidic vehicle at pH 6.0, the side effects observed in the former group were much severer than in the latter group. These data suggest that the antitumor effect of i.a. CQ chemotherapy can be potentiated by using an acidic vehicle.

Evaluation of multidisciplinary treatment of bladder cancer, especially in chemoimmunotherapy (ADM and OK-432) as a consolidation therapy.

The relapse rate of bladder cancer (transitional cell Ca) is said to be about 45%-80% even after tumor resection. Multidisciplinary treatment was designed and studied to prevent such recurrence. This treatment was designed to have three steps: induction, consolidation, and maintenance therapy. Following surgical tumor removal, OK-432 and Adriamycin (ADM) were administered as consolidation therapy, followed by administration of PSK and carboquone (CQ) in small amounts as maintenance therapy continuously for about 3 years, and the course was observed. In both consolidation and maintenance groups various non-specific immunoparameters were superior in groups receiving combined immunotherapeutic agents. Thus, the use of immunotherapeutic agents in combination with chemotherapeutic agents was considered to be effective. The 3-year recurrence rate was only 8% in the multidisciplinary treatment group, while that in the non-multidisciplinary treatment group was 61%. This approach, especially with chemoimmunotherapy (ADM and OK-432) as a consolidation therapeutic mode, is therefore considered to be useful for the prevention of recurrence.

[Regression of a recurrent malignant glioma by combined chemoradiotherapy utilizing carboquone, FT-207 and telecobalt--report of a case (author's transl)].

Current chemotherapy of malignant brain tumor bases on cell kinetics. Chemotherapeutic agents are devided into two, cell cycle specific (CCS) and cell cycle non specific (CCNS) agents. A case of malignant glioma successfully treated by chemo-radiotherapy using a new combination of the two agents , Carboquone (CQ) as CCNS, which has not appeared in literature, and FT-207 as CCS is reported. A malignant glioma in the right frontal lobe in a case of 51-year-old male was removed subtotaly on Dec. 10th, 1971 in our clinic. Three years and five months after the surgery, the patient was diagnosed as having a recurred malignant glioma in the left frontal lobe from the clinical symptoms. This was supported by a positive brain scan and carotid angiography. A total dose of 57mg of CQ was continuously into the left internal carotid artery during two months. Simultaneously, 16g of FT-207 as a total dose was given orally and 4,550 rads of Telecobalt-60 were irradiated. One month after the beginning of these treatments, clinical symptoms improved obviously. Four months later, the size of the tumor shadow on the brain scan decreased remarkably and the shifted anterior cerebral artery returned to normal position on the carotid angiogram. Anemia, leucopenia, thrombocytopenia, nausea, and anorexia were the side-effects of these treatments. But these complications disappeared six weeks after the termination of the treatments.

[Fundamental studies on intravesical instillation of carboquone for treatment of urinary bladder tumors--on the effects of intravesical instillation of carboquone in normal beagle dogs].

The effects of intravesical instillation of Carboquone at the clinically used doses of 5 and 10 mg on the normal mucosa of female beagle dogs was compared with that of 10 mg Mitomycin C used as the control drug. Intravesical instillation for 48 hours of 10 mg carboquone/20 ml phosphate buffer solution (PBS) after bilateral cutaneous uretrostomies produced severe inflammatory changes in all layers of the bladder wall. However, no secondary effects were observed in blood laboratory examinations or histological examinations of the whole organ after autopsy. Phosphate buffer solution produced no remarkable secondary effects in animals. Five milligrams carboquone per 20 ml PBS was instilled intravesically once a week for 3 weeks in normal animals. Cystoscopically , the bladder mucosa recovered normally. Blood laboratory examinations showed no abnormal results, but the bladder epithelium had regenerative epithelial hyperplasia and slightly inflammatory changes in the submucosal layers. Two of the three control animals given instillation of 10 mg of Mitomycin C/20 ml PBS had slight leucopenia at 7 days after the last intravesical instillation, but leucocyte count was normal at the end of the experiment. Cystoscopic and histological examination of the epithelium of the urinary bladder revealed severe inflammatory changes in 2 of the 3 animals.

[Combination chemotherapy with adriamycin, carboquone and 5-Fu for bladder cancer].

We treated 25 bladder cancer patients with combined cytotoxic chemotherapy of adriamycin (10--20 mg/day administration on days 1, 2 and 3), carboquone (4 mg/day administration on day 1 of weeks 3, 4 and 5 and 5-Fu (200 mg/day for 5 weeks) or futraful suppositories (750 mg/day for 5 weeks) as one course. According to the Koyama - Saitoh criteria, CR + PR was observed in 4 (17.4%) of 23 patients excluding the 2 dropout patients. According to Karnofsky's criteria, an effect with chemotherapy was observed in 9 (39.1%) of the 23 patients. There was a relatively good response rate in a group of 12 patients with the superficial tumors as compared with a group of 11 patients with the deep tumors. There were no severe adverse reactions.

[Study of combination chemotherapy with cytosine arabinoside in the intravesical treatment of superficial bladder tumors].

The effect of instillation therapy using CA alone or in combination with MMC, NCS or CQ was examined in 111 patients (92 males and 19 females, aged 32-87 years old with an average age of 66 years) with multiple superficial bladder tumors. The response rate of 29 patients given CA 400 mg alone was 48.3%, that of 25 patients given combination therapy of CA 200 mg and MMC 20 mg was 84.0%, that of 28 patients given combination therapy of CA 200 mg and NCS 4,000 U was 71.4%, that of 22 patients given combination therapy of CA 200 mg and NCS 6,000 U was 95.5% and that of 7 patients given combination therapy of CA 200 mg and CQ 10 mg was 100%. The response rates of the patients given any of the combination therapies were higher than that of the patients given CA alone. But because MMC, NCS and CQ were not administered singly, combination therapy cannot be concluded to be superior to single therapy. There was little difference between the response rate of primary cases and that of follow up cases. The side effects were all symptoms of local irritation, and were not indicative of systemic damage. Side effects were seen in 3.4%, 71.4%, 40.0% and 3.6% of the patients given CA alone, CA + CQ combination therapy, CA + MMC combination therapy and CA + NCS (4,000) therapy, respectively, combination therapy of CA and CQ producing the highest percentage of side effects.

[A case of advanced prostatic cancer presenting as inguinal mass].

A 71-year-old man visited our hospital complaining of a nodule in the left inguinal region. Pathological and immunohistochemical examination of the prostate and the mass and clinical examination revealed a case of prostatic cancer with lymph node metastasis, stage D. Chemoendocrine therapy (diethylstilbestrol diphosphate, cisplatin, adriamycin and carboquone) was performed and the patient responded well. This case indicated the presence of an unusual prostatic cancer in which large non-regional superficial lymph node metastasis occurred.

[Prophylactic intravesical chemotherapy in bladder tumors after surgery of upper tract urothelial carcinoma].

Sixteen patients with upper tract urothelial carcinoma underwent intravesical chemotherapy usually at 2 week intervals in the first year and at 4 week intervals in the second year after nephrouretectomy. For bladder instillation 10 mg mitomycin C in 20 ml saline was used on 7 patients, 5 mg carboquone and 100 mg cytosine arabinoside in 40 ml saline on 5 patients and 30 mg adriamycin in 40 ml saline on 4 patients. Two (12.5%) of the 16 patients developed bladder tumors within 2 years after surgery, but 11 (42.3%) of the 26 patients with upper tract urothelial carcinoma who did not receive intravesical chemotherapy suffered from bladder tumor within 2 years after surgery. Prophylactic intravesical chemotherapy reduced significantly (p less than 0.1) the incidence of bladder tumor after the surgery of renal pelvic and ureteral tumors.

[Experimental and clinical studies on intravesical instillation therapy for bladder cancer].

Intravesical instillation therapy was performed in 155 cases of urinary bladder cancer. In 60% of the patients treated by therapeutic intravesical instillation, antitumor effects were observed. The patients who were given only the instillation therapy frequently had recurrence of the tumor in the same site within one year. Therefore, in such cases prophylactic instillation seems to be necessary. The preventive effect of intermittent instillation therapy given over a long period was superior to that of concentrated instillation therapy given during a short period. The rate of recurring bladder tumors decreased after instillation therapy. Eight cases that were cystoscopically nonvisual tumors but indicated positive cytology were treated by intravesical instillation therapy. In 5 of these cases cytology was negative after treatment.

[The effect of intravesical chemotherapy on superficial urinary bladder cancer].

The effect of intravesical chemotherapy on superficial urinary bladder cancer was analysed. Fifty-nine patients with low-staged, low-grade bladder cancer were treated with intravesical instillation of three anticancer drugs (adriamycin, carbazilquinone and bleomycin). Complete response (CR) was observed in 15 out of 42 patients and partial response (PR) in 9 patients. Overall, a better response rate was observed with adriamycin and carbazilquinone than with bleomycin. Papillary tumors responded well to these intravesical chemotherapies compared to the non-papillary tumors . Intravesical recurrence of tumors was evaluated in 68 patients who received intravesical instillation of these three drugs after TUR of tumors. The actuarial recurrence rate of 68 patients was 11, 22 and 34% within 1, 2 and 3 years, respectively. These rates were significantly lower than that of TUR therapy alone. No serious side effect was seen in these patients. From these results, it is noted that intravesical chemotherapy is a useful approach for controlling superficial urinary bladder cancer.

[Megakaryoblastic transformation associated with disseminated intravascular coagulation in the course of polycythemia vera: a case report].

A 57-year-old male who had suffered from polycythemia vera (PV) and had been treated with pipobroman, carbazilquinon and busulfan for ten years presented with fever. CBC revealed anemia and thrombocytopenia without an increase of leukemic blasts (WBC, 7,700/microliters, RBC 294 x 10(4)/microliters, Hb 9.1 g/dl, Plt 1.5 x 10(4)/microliters). Bone marrow aspiration resulted in dry tap. Bone marrow biopsy showed hyperplastic marrow with fibrosis and no increase in leukemic blasts. Eleven days later the patient became leukemic and he died of DIC. Blast cells showed a high nucleo-cytoplasmic ratio, basophilic cytoplasm and cytoplasmic blebs. Cytochemical and immunophenotype analysis of the blast cells showed the following results; myeloperoxidase (-), chloroacetate esterase (-), Sudan black (-), acid phosphatase (+), acetate esterase (+), PAS (+), HLA-DR (+) and GPIIb/IIIa (+). Platelet peroxidase reaction on electron microscopy was positive in perinuclear spaces and endoplasmic reticulum. A diagnosis of megakaryoblastic transformation of PV was made. Although acute myelogenous leukemia has been shown to develop occasionally in the course of PV, acute megakaryoblastic leukemia with DIC following PV is a very rare condition.

[A case of relapsed pulmonary carcinoma showing an interesting chemotherapeutic course].

A patient with relapsed primary pulmonary carcinoma (T2N0M0 Stage II adenocarcinoma) showing contralateral metastasis after 4 postoperative years was given Carboquone (CQ), Cisplatin (CDDP) and OK-432, and positive therapeutic results were obtained. However, aggravation ensued and so UFT was given in combination with the above chemotherapy, resulting in repeatedly good results. The details of this case of relapsed pulmonary carcinoma, which was resistant to chemotherapy but showed positive therapeutic results with combined use of UFT, are reported.

[An anticancer drug--carboquone].

Carboquone (CQ) is an anticancer alkylating agent synthesized and developed by Arakawa et al. (Sankyo Co, Ltd.) in 1970, having chemical structure, 2,5-bis-(1-aziridinyl)-3-(2-carbamoyloxy-1-methoxyethyl)-6-methyl- 1,4- benzoquinone. The antitumor efficacies of CQ were reported as excellent, however, the side effects are considerably strong. For the purpose to increase the effectiveness and to eliminate the side effect, various treatment regimen with CQ have been reported. Combination chemotherapies including CQ and cis-Platinum etc. have been reported to increase the antineoplastic activity and CQ combined with immunopotentiator or prednisone have been reported to diminish the side effects. The regimens of PPQ therapy in our department is as follows. CQ is given 7 mg/m2 iv on day 1; cis-Platinum 20 mg/body, drip infusion on day 1-5. Prednisone 3.0 mg p.o. on day 1-5. The response rate found in this regimen was about 30% so far. Antitumor spectrum of this drug has been reported to become broad.

[Intravesical instillation of adriamycin and other antineoplastic agents].

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.

[Effect of carboquone (esquinone) on the development of urinary bladder tumors in rats induced by N-butyl-N-(4-hydroxybutyl) nitrosamine].

The effect of carboquone (CQ) by intraperitoneal 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 9 of 11 rats (81.8%) when they were given 0.05% BBN in drinking water for 8 weeks and then given water without BBN for 12 weeks. When CQ 0.25 mg/kg/day was administered intraperitoneally for 7 days after treatment with 0.05% BBN for 8 weeks, incidence of urinary bladder tumors was 19 of 26 rats (73.1%). When CQ 0.25 mg/kg/weekly was given for 12 weeks after treatment with BBN, incidence of urinary bladder tumors was 17 of 27 rats (63.0%). When CQ 0.5mg/kg. B.W./day was given for 7 days after treatment with BBN, tumors developed in the urinary bladder with low incidence as in 8 of 20 rats (40.0%) (P 0.1). When CQ 0.5mg/kg/weekly was given for 12 weeks after treatment of BBN, urinary bladder tumors were induced in 17 of 22 rats (77.3%). Hematotoxity was not observed in any animals treated with CQ. These results showed that CQ inhibited the development of urinary bladder tumors induced by BBN in rats.

[Experimental study on immunochemotherapy (PSK, CQ) in rat bladder cancer (BC-47)].

Cancer of the urinary bladder is a tumor with the highest frequency among urogenital cancers, and more-over, its recurrence rate is high. It is considered important and urgently necessary to conduct studies into the prevention of recurrence of this cancer. We have started a Study Group on Postoperative Maintenance Therapy for Bladder Tumor (Tokyo), and conducted group studies on the prevention of recurrence. Fundamental experiments have been performed, and the following results obtained. Antitumor effects of PSK in combination with CQ for bladder carcinoma were studied using male ACI rats. An established bladder carcinoma cell line, BC47 was transplanted into the backs of rats subcutaneously prior to the administration of PSK and CQ. Inhibitory effect on tumor growth and prolongation of survival period were examined. Although single-agent PSK or CQ both had inhibitory effects on transplanted tumors as well as on metastatic tumors in the lung, more remarkable effects were noticed as a result of combination treatment. Prolongation of lifespan using combination therapy was superior to that using single treatment and the rats of decrease in body weight was also lower. These results do not necessarily clarify the antitumor mechanisms, but the immune system, probably non-specifically, may take part in the mechanism judged from the accumulated results obtained from in vivo systems. We think that the combinational effects of these two drugs on general condition are probably originated from inhibition of tumor growth since the inhibition, prolongation of lifespan, change of body weight and so on were closely correlated with each other. However, the direct effect of these drugs may also be counted. The combination therapy of PSK and CQ seemed to be useful against rat bladder carcinoma, BC47. We therefore intend to proceed with group study trials of Postoperative Maintenance Therapy for Bladder Tumor.

[Combination therapy of high-dose carboquone and OK-432 in unresectable non-small cell lung cancer].

A combination of OK-432 and high-dose Carboquone (12-22 mg/m2) was administered to 17 patients with unresectable non-small cell lung cancer. The response rate was 42.9% (CR-1, PR-5) among 14 patients in whom measurement of tumor diameter was possible. With regard to hematologic adverse effects, 13 patients had a WBC count of less than 3,000, and 6 patients had a platelet count of less than 50,000. Duration of WBC nadir was not longer than 3 days, and there were no cases of infectious complication or bleeding tendency. Other side effects were all transient.

[A case report of patient with advanced stomach carcinoma of linitis plastica type responding to multi-immunotherapy and chemotherapy].

Multiple-drug (OK-432, PSK and SPG) immunotherapy and chemotherapy provided remission of symptoms for 36 months in a patient aged 21 years suffering scirrhous gastric carcinoma associated with carcinomatous peritonitis in which direct infiltration to the pancreas, retroperitoneum and the left colon was observed. A remarkable improvement with time was observed by endoscopic and roentgenographic observation, and a substantial improvement was also observed in the NK-cell ratios of lymphocyte subsets of the OKT series in relation to immunologic parameters. A tumor necrosis factor [TNF]-like substance was thought to have been induced by multiimmunotherapy in this case.

[Clinical results of a randomized controlled trial on the effect of adjuvant immunochemotherapy using Esquinon and Krestin in patients with curatively resected gastric cancer--7-year survival--Cooperative Study Group for Cancer Immunochemotherapy, Tokai Gastrointestinal Oncology Group].

A randomized controlled study was carried out on curatively resected gastric cancer patients in a cooperative study involving 16 institutions in order to evaluate the effect of an alternative long-term adjuvant immunochemotherapy using Esquinon (CQ) and Krestin (PSK). One week after surgery, CQ was given at a dose of 2mg/m2 once a week for 3 weeks and this was repeated every 6 weeks. CQ was administered intravenously in the 1st course and thereafter orally up to 9 courses. Three postoperative week, immunotherapy was then started in which PSK was given orally in 3 divided doses of 2g/m2/day from the day when CQ therapy ended for 4 consecutive weeks, and this performed for every course. Estimated survival rate and cumulative survival curves were compared utilizing the data up to 7 years after surgery in the chemotherapy group given CQ alone and in the immunochemotherapy group given CQ + PSK. The survival curve in all cases showed a favorable form in the CQ + PSK group for up to 36 months, and thereafter it crossed with that of the CQ group for up to 68 months. Both curves twisted at 68 months and then deviated from each other, showing that the effect in the CQ + PSK group beneficial. The curve showed a twisting configuration throughout the treatment period. There was no statistically significant difference between the survival curves of the two groups. Retrospective survival analysis was then performed on separate subgroups classified into the category of S1, S2, N1, and N2. The CQ + PSK group was better than the CQ alone group in its survival rate for the S1 + S2 (N1-2) group, the percentage being 11.5%, and a statistically significant difference was observed between the two groups (p = 0.089).