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.

Essential thrombocythemia transformed to acute myelogenous leukemia with t(3;17)(p24; q12), del(5)(q13q34) after treatment with carboquone and hydroxyurea.

In 1991, a 52-year-old woman was diagnosed as having essential thrombocythemia (ET). She was doing well with continuous medication with carboquone (CQ) and subsequently hydroxyurea (HU). However, substantial leukocytosis with leukemic blast cells, anemia and thrombocytopenia developed in 1996. Analysis of peripheral blood showed 4.4 x 10(3)/microl white blood cells with 82% of leukemic blast cells. These blasts showed negative staining with myeloperoxidase by immunostaining, but the myeloperoxidase was positive by electron microscopic analysis. Cytogenetic analysis of bone marrow cells revealed a t(3;17)(p24; q12), del(5)(q13q34). On the basis of these findings, the leukemic blast cells were classified as acute myelogenous leukemia (AML:M0) in the FAB classification. The causative agent, CQ and HU in secondary leukemia from ET and chromosomal abnormality related to ET blastic crisis (BC) are discussed.

Potentiation of the cytotoxicity of carboquone by flavone acetic acid combined with hyperthermia.

Flavone acetic acid (FAA) has shown the effectiveness of vasoactive drugs in the selective reduction of tumor blood flow. A FAA-mediated decrease in tumor blood flow may produce sufficient hypoxic conditions within the tumor. Carboquone (CQ), a naturally occurring prototype bioreductive alkylating agent like mitomycin C (MMC), has been shown to be selectively more cytotoxic toward hypoxic tumor cells. We have reported enhancement of the combined antitumor effects of MMC plus FAA and hyperthermia (HT). In this study, we examined the combined effects of FAA, CQ and HT. In vitro, although HT (43 degrees C, 60 min) reduced the colonogenicity to 0.58 in CQ (0.01 microg/ml) alone, the combined cytotoxicity of CQ and HT was not enhanced with exposure to FAA at a concentration of 100 microg/ml. In vivo, the tumor growth time, calculated as the time required to reach twice the initial tumor volume, for CQ (2 mg/kg) alone, FAA (150 mg/kg) alone, CQ+FAA, CQ+HT (43 degrees C, 15 min), FAA+HT and FAA+CQ+HT was 6.1, 5.1, 7.1, 8.0, 7.6 and 13.4 days, respectively. A significant enhancement of antitumor effects by trimodality therapy with CQ, FAA and HT was observed, when compared to the treatment with CQ and FAA (p < 0.05). The possible mechanisms of an increased antitumor response achieved with the combination of CQ, FAA and HT may be explained in the following way: the FAA-mediated decrease in tumor blood flow produced sufficient hypoxic conditions within the tumor, and these resulted in a significant increase of the antitumor effects of CQ and HT.

A prospective study of surgery and adjuvant chemotherapy for primary gastric lymphoma stage II.

The standard management of primary gastric lymphoma (PGL) (stage II) has not been established despite the use of various treatment modalities. The present prospective trial of combined surgery and chemotherapy for the treatment of PGL (stage II) included 25 consecutive patients treated between July 1978 and December 1993. Twenty-one patients were treated with total gastrectomy and four with partial gastrectomy; this was followed by post-operative chemotherapy with m-VEPA (vincristine, cyclophosphamide, prednisolone and doxorubicin), followed by consolidation chemotherapy with VEMP (vindesine, cyclophosphamide, methotrexate and prednisolone) or VQEP (vindesine, carbazilquinone, cyclophosphamide and prednisolone). Twenty-one of the 25 patients who completed post-operative chemotherapy were free of relapse 26-203 (median 94) months after the gastrectomy. Of the four patients who did not complete the projected chemotherapy, two relapsed and died of lymphoma. Another patient with recurrent lymphoma died in an accident, and the fourth patient was in remission at 54 months after surgery. The post-operative overall and disease-free survival rates at 10 years for the 25 evaluable patients were 81.6% and 92.0% respectively. Major surgical complications and treatment-related death after chemotherapy were not observed. PGL (stage II) appears to be curable when treated with gastrectomy and adjuvant chemotherapy.

[Experimental study and clinical application of a new combination chemotherapy with cis-platinum, adriamycin and carboquone in patients with advanced prostate cancer].

In vitro chemosensitivity of established cell lines from human prostate cancer (8 PC 93, 19 PC 93, DU 145 and PC 3) to various anticancer drugs was examined by clonogenic assay. The drugs used were aclarubicin (ACR), adriamycin (ADM), carboquone (CQ), vincristine (VCR), ifosfamide (IFM), peplomycin (PEP) and cis-platinum (CDDP). To compare antitumor activity of different drugs, the predicted anticancer activity (PAA) was calculated from the 50% inhibition doses and the peak plasma concentration of the clinically used dose. High antitumor activity of drug was considered if PAA > or = 1 was observed. The chemosensitivities were: CQ > ADM > CDDP > VCR > PEP > IFM > ACR in the clonogenic assay. 19 PC 93 and DU 145 were sensitive to CQ, ADM and CDDP, but 8 PC 93 and PC 3 were sensitive to CQ, ADM, CDDP and VCR. Thus, a new combination chemotherapy with CDDP, ADM and CQ (PAQ therapy) was used clinically. PAQ therapy was given to sixteen patients with stage D advanced prostate cancer. Of these patients, 14 were undergoing relapse from antiandrogen therapy and 2 had hormone-resistant prostate cancer. The mean interval from the start of the prior treatment to relapse of the cancer was 18 months. The effectiveness of the new therapy was judged according to the response criteria for prostate cancer treatment of Japan. Three patients showed partial response (PR), 9 were stable disease (Stable) and 4 showed progressive disease (PD). The mean response duration in the patients with PR and with Stable was 11.6 months. The survival length of the responders (PR + Stable) was significantly longer than that of the nonresponders (PD) (p < 0.001). The side effect of PAQ therapy was lower than the moderate degree. Therefore, we considered PAQ therapy to be one of the clinical trials for the treatment of advanced prostate cancer.

The subrenal capsule assay in selecting chemotherapy for ovarian cancer: a prospective randomized trial.

In order to find out whether the response rate and survival in epithelial ovarian cancer can be improved by aid of sensitivity testing with the subrenal capsule assay (SRCA), 196 patients with FIGO Stage II-IV epithelial ovarian cancer were randomized to be treated with either cyclophosphamide-doxorubicin-cisplatin (CAP) or SRCA-guided chemotherapy. The drug combinations tested with the SRCA were (1) cyclophosphamide-doxorubicin-carboplatin (CACAR), (2) CAP, (3) carboquone-methotrexate-tegafur (CQ-MTX-TEG), (4) cisplatin-etoposide-hexamethyl-melamine (P-VP-HXM), and (5) bleomycin-epirubicin-cisplatin (BEP). A total of 132 patients (CAP, 69; SRCA, 63) were eligible for efficacy analysis based on relaparotomy findings. The overall response rate was 59% in the CAP arm and 62% in the SRCA arm. In the SRCA arm, 16 patients were treated with CACAR, 24 with CAP, 10 with CQ-MTX-TEG, 11 with P-VP-HXM, and 2 with BEP. The response rate to CACAR was 63% and to SRCA-CAP was 75%. The number of complete responses was higher when CAP was given as guided by the assay than when given at random (14/24 vs 23/69; P = 0.03, Pearson chi 2). Survival curves as estimated by Kaplan-Meier method gave a median survival of 24 (SE = 4) months to the SRCA arm and 28 (SE = 5) for the CAP arm (P = 0.7; log-rank test). Because no survival benefit was achieved, the SRCA obviously needs further development before it can be routinely recommended in the choice of first-line chemotherapy for patients with ovarian cancer.

[Post-operative intra-arterial chemotherapy for high grade malignant musculoskeletal sarcoma].

Twenty-nine patients with high grade malignant musculoskeletal sarcoma were treated with chemotherapy. Intra-arterial chemotherapy was performed post-operatively for patients with local recurrence, patients with poor response to pre-operative chemotherapy or patients with intra-lesional or marginal surgical margin. The local recurrence rate in patients with intra-arterial chemotherapy (8.8%) was lower than in those with intravenous chemotherapy (37.5%). Patients with post-operative intra-arterial chemotherapy showed no local recurrence. Of the 29 patients except stage 3 with intra-arterial chemotherapy, the metastatic rate in patients with intra-arterial chemotherapy (41.4%) was lower than in chemotherapy patients with intravenous chemotherapy (83.3%). The rate in the post-operative group (28.6%) was lower than in the pre-operative group (42.9%) or pre- and post-operative group (50.0%). The ten-year survival curve of patients given intra-arterial chemotherapy (51.0%) was higher than in patients on intravenous chemotherapy (17.9%). Among the 34 patients who underwent intra-arterial chemotherapy, the survival rate in the other pre- and post-operative groups and the post-operative group (55.6%) was higher than in the pre-operative group and pre- and post-operative group (49.8%).

[A case of hyperosmolar nonketotic coma occurring during chemotherapy in lung cancer].

A 61-year-old woman was admitted to our hospital because of hoarseness and abnormal shadow on chest X-ray. We diagnosed this patient as large cell carcinoma of the right upper lobe of the lung; T3N3M1 Stage IV. She was treated with OK-432, CDDP and CQ. On the 6th day after 2nd cycle chemotherapy, she was confused, and we diagnosed her as a case of hyperosmolar nonketotic coma (HNC) on the 7th day. Unfortunately, she died on the 8th day, after 20 hours of treatment for HNC. She suffered from chronic dehydration due to trouble with left recurrent nerve palsy. Although continuous intravenous hyperalimentation was used, she had severe HNC. HNC might be one complication in chemotherapy for patients with malignancy.

[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.

Cytotoxicity of mitomycin C and carboquone combined with hyperthermia against hypoxic tumor cells in vitro.

Enhancement of the cytotoxicity of mitomycin C (MMC) and carboquone (CQ) by hypoxia at elevated temperature was examined using the SDI test of mouse Sarcoma 180 and Ehrlich cells and clonogenic assay of HeLa cells. When Sarcoma 180 and Ehrlich cells were incubated at 43 degrees C for 2-10 h, the hyperthermic effect was enhanced by hypoxia. The succinate dehydrogenase activity of the cells was reduced by hyperthermia to a greater extent in the presence of hypoxia (O2:5%) than under conditions of aeration (O2:20%). When the cells were exposed to various concentrations of MMC and CQ, under hypoxia, activity of the drugs was enhanced compared to the findings under conditions of aeration. The enhancement was prominent in case of drugs and hyperthermia combined. Clonogenicity of hypoxic HeLa cells was also reduced to a greater extent with this combination than in case of aerated cells. We tentatively speculate that hyperthermo-chemotherapy using MMC and CQ has a potential to attack selectively hypoxic cells present in a solid tumor.

An analysis of first-order release kinetics from albumin microspheres.

Release rates from BSA microspheres prepared from various conditions are analysed using a previously reported equation expressing the first-order release rate constant. The permeability constants calculated applying the equation on experimental release rates are in good agreement with the constants measured from permeation studies using planar membrane, for various preparation conditions. It is shown that the equation expressing the first-order release rate constant is valid more extensively. The permeability constant varies depending on the preparation conditions, and the reason for variation is shown clearly to be the difference in degree of swelling of the polymer. It was found from regression analysis that there is relatively simple correlation between unknown parameters of the equation and the preparation conditions. Release rate constants can be calculated applying the equation on the known parameters and the estimated values of the unknown parameters from the correlation. Good agreement was found between the calculated values and experimental ones; therefore, at least as far as we examined here, the release rate constant of the microsphere can be estimated from the preparation conditions.

[Cases of advanced cholangiocarcinoma showing partial response by the combination chemotherapy including protracted continuous infusion of 5-FU combined with intravenous administration of low-dose leucovorin and intra-arterial administration of MMC and CQ].

We treated a patient with advanced cholangiocarcinoma with a new combination chemotherapy (modified MQF). The regimen consisted of intra-arterial administration of MMC (20 mg/body) and CQ (4 mg/body), protracted continuous infusion of 5-FU (500 mg/body) and intravenous administration of low-dose leucovorin (30 mg/body). More than 50% reduction in the liver tumor for over 4 weeks was obtained by the therapy. As for toxicity, diarrhea and stomatitis were observed.

A new concept for interpretation of first-order release from albumin microspheres.

A release mechanism from a microsphere that consisted of a water-swellable polymer and a uniformly dispersed, relatively small number of very slightly soluble large-core particles was considered. When the microsphere is dipped in release media the polymer swells instantly, and every core particle dissolves in the release media in the space between the core particles and the swollen polymer to make a saturated solution. It is assumed that Fickian diffusion of dissolved core substance between all spaces filled with saturated solution and outer sink occurs independent of each other, and release from one entire microsphere is the sum of diffusion from all spaces in the microsphere. Then, derived theoretical release kinetics is found to be first-order, and the derived first-order release rate constant is expressed as a function of the following parameters: radius of core particle, radius of the microsphere, solubility of core substance to media solution, density of the core particle, and permeability constant of core substance in swollen polymer. When rate constants were measured from release tests, varying each parameter, the relation between constants and each parameter follows the function. The permeability constant, which was calculated applying the function on measured rate constants and other known parameters, was in good agreement with the permeability constant measured from permeation study of planar membrane prepared in similar conditions to when preparing microspheres. These results are thought to show the validity of the mechanism and function proposed.

[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.

Alternating immunochemotherapy of advanced gastric carcinoma: a randomized comparison of carbazilquinone and PSK to carbazilquinone in patients with curative gastric resection.

A total of 103 patients with advanced gastric carcinoma were randomized after curative surgery to receive an alternate administration of carbazilquinone (CQ) and PSK (Krestin) or carbazilquinone alone. Each course of therapies started 1 week after the surgical operation and therapy schedules consisted of 9 courses. In each course of 6 weeks, CQ (2 mg/m2/week) was administered on day 0, 8, and 15. In combined immunochemotherapy group, PSK was given orally in 3-divided doses of 2 g/m2/day from the day of the third CQ administration for consecutive 4 weeks. Estimated survival rate and cumulative survival curve were compared utilizing the data up to 7 years after the operation. There was no overall significant difference in survival rates between the CQ plus PSK group and the CQ alone group, but a group of patients whose disease was classified as S1 + S2(N1-2) survived significantly longer when treated with the combination of CQ and PSK. Neither in more advanced cases (greater than S3 or greater than N3) nor in cancers of early stages, the addition of PSK provided an additive effect. The favorable result obtained in one subgroup treated with PSK, suggests that the use of this agent in treating gastric cancers should be carefully evaluated in terms of serosal infiltration and nodal metastasis.

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.