aclarubicin and Prostatic-Neoplasms

The nuclear enzyme DNA topoisomerase II is a major target for antineoplastic agents. All topoisomerase II-directed agents are able to interfere with at least one step of the catalytic cycle. Agents able to stabilize the covalent DNA topoisomerase II complex (also known as the cleavable complex) are traditionally called topoisomerase II poisons, while agents acting on any of the other steps in the catalytic cycle are called catalytic inhibitors. Thus, catalytic topoisomerase II inhibitors are a heterogeneous group of compounds that might interfere with the binding between DNA and topoisomerase II (aclarubicin and suramin), stabilize noncovalent DNA topoisomerase II complexes (merbarone, ICRF-187, and structurally related bisdioxopiperazine derivatives), or inhibit ATP binding (novobiocin). Some, such as fostriecin, may also have alternative biological targets. Whereas topoisomerase II poisons are used solely for their antitumor activities, catalytic inhibitors are utilized for a variety of reasons, including their activity as antineoplastic agents (aclarubicin and MST-16), cardioprotectors (ICRF-187), or modulators in order to increase the efficacy of other agents (suramin and novobiocin). In this review, the mechanism and biological activity of different catalytic inhibitors is described, with emphasis on therapeutically used compounds. We will then discuss future development and applications of this interesting class of compounds.

Topics: Aclarubicin; Antineoplastic Agents; Breast Neoplasms; DNA Topoisomerases, Type II; Enzyme Inhibitors; Female; Hematologic Neoplasms; Humans; Lung Neoplasms; Male; Piperazines; Prostatic Neoplasms; Sarcoma; Topoisomerase II Inhibitors

In May 2006, a 72-year-old man with acute myelogenous leukemia (M4Eo) was admitted to our hospital. He had been receiving antiandrogen treatment for prostate cancer (after an operation in 1998) and treatment for diabetes mellitus. He received chemotherapy according to the JALSG GML200 protocol, which led to complete remission; however, in January 2007, his leukemia recurred. CAG combination chemotherapy also resulted in complete remission by May 2007. In August 2007, he developed multiple liver tumors, abdominal pain, and fever. Contrast-enhanced computed tomography revealed hypovascular tumors in both early and delayed phases. Angiography showed ring-like tumor staining and a massive tumor, similar to those seen in metastatic hepatocellular carcinomas (HCCs). He eventually died because of aggressive enlargement of liver tumors during the following month accompanied by the simultaneous recurrence of leukemia and unsuccessful embolization of the hepatic artery. Autopsy specimens showed fibrosis and considerable iron deposition in the liver, suggested secondary hemochromatosis due to transfusion. We also detected multiple moderately differentiated primary HCCs. Secondary hemochromatosis, androgen imbalance, and humoral factors from leukemic cells were believed to be the causes of the rapid onset and development of HCCs.

Topics: Aclarubicin; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cytarabine; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Hemochromatosis; Humans; Leukemia, Myeloid, Acute; Liver Neoplasms; Male; Neoplasms, Second Primary; Prostatic Neoplasms; Time Factors

Prostate cancer patients were treated with a basic therapy of intra-arterial injection of neocarzinostatin (NCS). This therapy was divided into three types of regimen: NCS intra-arterial injection alone, NCS intra-arterial injection + diethylstilbestrol (DES), and NCS intra-arterial injection + aclacinomycin A (ACR) + peplomycin (PEP). A comparative study was carried out on the clinical efficacies of these three regimens, and at the same time an investigation was made of the prognosis in the cases receiving NCS intra-arterial injection alone and NCS + DES. The clinical efficacy was found to be high in each of the three treatment groups in terms of subjective symptoms and laboratory findings, except for ALP. In the evaluation of efficacy on the basis of histological findings, the rates were 60.0% for NCS intra-arterial injection alone, 71.4% for NCS + DES, and 88.2% for NCS + ACR + PEP. Thus, all three of these treatment regimens gave good efficacy rates, but it is especially noteworthy that the combined chemotherapy regimen yielded the highest efficacy rate. On the other hand, the incidence of adverse reactions was much higher in the case of the combined chemotherapy regimen than in the other two regimens. In the patient group administered the NCS intra-arterial injection alone, the one-year survival rate was 75.0% and the 4-year survival rate was 25.0%, while in the NCS + DES treatment group the one-year survival rate was 87.5% and the 4-year survival rate was 37.5%. For individual patients, the correlation between the clinical efficacy and the prognosis was not strong. However, it was concluded that all three of the chemotherapy regimens are useful as forms of remission induction therapy.

Topics: Aclarubicin; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Diethylstilbestrol; Humans; Injections, Intra-Arterial; Male; Middle Aged; Naphthacenes; Peplomycin; Prognosis; Prostatic Neoplasms; Zinostatin

Male F1 hybrid rats bearing the R-3327 transplantable prostatic adenocarcinoma demonstrating similar growth patterns within the original sample of animals were carefully separated into control and treatment groups. This assured treatment of tumors with similar cell kinetics within each group. In the first study, two separate drug protocols were investigated by intraperitoneal injection, namely cyclophosphamide (100 mg/kg) once every 4 weeks for 8 weeks and scheduled methotrexate (7.5 mg/kg) followed in 90 minutes by 5-fluorouracil (50 mg/kg) once each week for 8 weeks. Excellent suppression of tumor growth was obtained with each treatment protocol. Both were significant at the 0.01 level. In the second study, methotrexate (100 mg/kg) intraperitoneally once each week for 6 weeks, aclacinomycin-A intraperitoneally once each week for 4 weeks, and ketoconazole (60 mg/kg) via gavage 5 times a week for 6 weeks were administered to the animals in each respective group. Aclacinomycin-A and ketoconazole showed significant suppression of tumor growth at the 0.01 and 0.05 levels, respectively. Methotrexate suppressed tumor growth, but did not reach levels of significance over the duration of the study (0.2 less than P less than 0.3).

Topics: Aclarubicin; Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Administration Schedule; Fluorouracil; Ketoconazole; Male; Methotrexate; Naphthacenes; Neoplasm Transplantation; Prostatic Neoplasms; Rats