aclarubicin and Colonic-Neoplasms

Clinical evaluation of the combination chemotherapy of ACM and 5-FU(AF therapy) for patients with far-advanced, recurrent and inoperable gastric and colorectal carcinomas was made by the study group composed of 13 major hospitals in Tohoku area. Fifty-nine patients were treated with this regimen and 41 (gastric carcinoma 32 cases, colorectal carcinoma 8 cases and bile duct carcinoma 1 case) were evaluable. The schedule of treatment was as follows: 40mg of ACM was given twice a week (the 1st and 4th days) by intravenous one-shot injection along with 250mg of 5-FU everyday by intravenous drip infusion. No patients received anti-cancer drugs and radiation therapy for one month before AF therapy. As to the clinical efficacy, 32 patients with gastric carcinoma showed a relatively good response rate of 3% on CR and 22% on PR by Koyama and Saito's criteria. The rate that showed more than I-A by Karnofsky's criteria was 38%. The clinical effects on patients with colorectal carcinoma or bile duct carcinoma were negligible. As to the histological types, 16 cases with poorly-differentiated gastric carcinoma showed a response rate of 6% on PR, but 16 patients with well a differentiated gastric carcinoma showed that of 38% of PR and 6% of CR. The effective cases were more frequently observed in well-differentiated carcinoma than poorly-differentiated carcinoma. The major side effects of AF therapy were bone marrow suppression and gastrointestinal toxicity. The former was observed in 45% of all patients and the latter in 27% of them. Hepatic toxicity, abnormal change of ECG and hemorrhagic diathesis were not observed.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Bile Duct Neoplasms; Clinical Trials as Topic; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Gastrointestinal Neoplasms; Humans; Naphthacenes; Rectal Neoplasms; Stomach Neoplasms

The present study was undertaken to determine if (a) genistein induces topo II-mediated DNA damage in HT-29 colon cancer cells; and (b) if this damage is required to induce apoptosis. DNA damage was evaluated using the comet assay. Apoptosis was determined by the ethidium bromide/acridine orange staining technique. DNA breakage was noted within 1 h of treatment. Apoptosis was only induced with high concentrations (>/=60 microM) of genistein. Marked inhibition of HT-29 cell growth was evident at concentrations ranging from 60 to 150 microM. This was associated with a cell cycle arrest at G(2)/M. Similar findings were obtained in SW-620 and SW-1116 colon cancer cell lines. Aclarubicin, a topo II antagonist, reduced genistein-induced DNA breaks but did not reduce apoptosis. These data suggest that, in colon cancer cells, topo II serves as the enzymatic target of genistein. Furthermore, topo II-mediated DNA cleavage is not required for the induction of apoptosis.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Division; Colonic Neoplasms; DNA Damage; DNA Topoisomerases, Type II; DNA, Neoplasm; Dose-Response Relationship, Drug; Genistein; Growth Inhibitors; Humans; Tumor Cells, Cultured

Aclacinomycin A (ACM), a potent inducer of leukemic cell differentiation, significantly enhances the radiosensitivity of a human colon tumor cell line (Clone A) when cultures are exposed to 15-nM concentrations for 3 days before irradiation. We now demonstrate that incubation with ACM after irradiation can also enhance Clone A cell killing. The maximum increase in cell killing, based on colony-forming ability, occurred when Clone A cells were exposed for 1 h to 5 microM ACM added 1 or 2 h after irradiation. The post-irradiation ACM protocol reduced the terminal slope (as reflected by D0) of the radiation cell survival curve with no change in the low-dose, shoulder region of the curve (Dq value). In contrast, for pre-irradiation treatment with ACM (15 nM, 3 days), the shoulder region of the curve was reduced with no change in the terminal slope. For pre- and post-irradiation ACM treatment the dose enhancement factors at 0.10 survival were 1.22 and 1.28, respectively. When ACM was given both before and after irradiation both the shoulder and terminal slope values decreased to produce a dose enhancement factor at a surviving fraction of 0.10 of 1.50. These data suggest that the enhanced cell killing produced by pre- and post-irradiation treatment with ACM is achieved through different mechanisms.

Topics: Aclarubicin; Cell Survival; Clone Cells; Colonic Neoplasms; Gamma Rays; Humans; Radiation Dosage; Radiation Tolerance; Tumor Cells, Cultured

Breast and colon tumor response to emoxyl, a nitroxyl derivative of daunomycin, was detected using human tumor heterotransplantation under the renal capsule of immunocompetent mice. The substitution of adriamycin by emoxyl in the combined therapy led to enhanced therapeutic efficacy. The evidence of enhanced response of breast tumors to emoxyl obtained during the histologic examination of xenografts is in good agreement with measurements of tumor fragment weight. It is suggested to use a quantitative kinetic index kappa calculated by the method of equivalent exponents for objective evaluation of tumor response to the drugs.

Topics: Aclarubicin; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Colonic Neoplasms; Cyclophosphamide; Daunorubicin; Dose-Response Relationship, Drug; Doxorubicin; Evaluation Studies as Topic; Fluorouracil; Humans; Mice; Neoplasm Transplantation; Subrenal Capsule Assay

The cytotoxic activities of several natural and semisynthetic anthracyclines against L1210 leukemia and two human colon tumor cells (Colon 4, HT 29) in vitro were examined after short (1 h) and long (7 days) incubation times and correlated with the water/octanol partition coefficients and the DNA-binding affinity of the compounds. Analysis of equation in which cytotoxicity against L1210 (1-h incubation) was parabolically related to the partition coefficient revealed an almost exclusive correlation (r = 0.80) between the cytotoxicity and the parameters, and this correlation was only slightly improved by addition of DNA-binding affinity (r = 0.85). On the other hand, cytotoxic activities displayed after continuous incubation were partially related to both partition coefficients (parabolic dependence) and DNA-binding affinities (linear dependence). In this case the correlation between the activity and partition coefficient (r = 0.67) was significantly improved by addition of DNA-binding affinity (r = 0.90). Similar results were also obtained for human colon tumor cells although the corresponding correlation coefficients were generally of lower value, indicating that cytotoxic activity of anthracyclines against these primary resistant cells may be influenced by additional factors not yet determined.

Topics: Animals; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry, Physical; Colonic Neoplasms; DNA; Humans; Leukemia L1210; Molecular Structure; Neoplasms; Regression Analysis; Structure-Activity Relationship; Tumor Cells, Cultured

The sensitivity to 1-hexylcarbamoyl-5-fluorouracil (HCFU) of 25 colorectal cancer tissues was compared with that of six antitumor drugs: carboquone (CQ), Adriamycin (ADM), mitomycin C (MMC), aclacinomycin A (ACR), cisplatin (DDP), and 5-fluorouracil (5-FU), using the in vitro succinate dehydrogenase inhibition (SDI) test. Chemosensitivity was determined to be positive when the succinate dehydrogenase (SD) activity of the drug-exposed cells, at ten times the peak plasma concentration, was decreased to below 50 percent of that of control cells on day 3 of exposure. Decrease in SD activity was remarkable in cases of exposure to HCFU, compared with six other drugs. The sensitivity rates were 32 percent for CQ, 40 percent for ADM, 24 percent for MMC, 28 percent for ACR, 32 percent for DDP, 16 percent for 5-FU, and 68 percent for HCFU. The sensitivity rate for at least one of the six drugs (CQ, ADM, MMC, ACR, DDP, and 5-FU) was 52 percent, but was 80 percent when HCFU was taken into account. Since colorectal cancer tissues are resistant to various antitumor drugs, the chemosensitivity test of HCFU should aid in determining the effects of a particular drug for an individual patient.

Topics: Aclarubicin; Antineoplastic Agents; Carbazilquinone; Cisplatin; Colonic Neoplasms; Doxorubicin; Drug Screening Assays, Antitumor; Fluorouracil; Humans; In Vitro Techniques; Mitomycin; Mitomycins; Naphthacenes; Rectal Neoplasms; Succinate Dehydrogenase

Thirty-two patients with measurable metastatic colorectal cancer refractory to 5-fluorouracil-containing regimens received aclacinomycin A (ACM-A) on a single-dose I.V. schedule administered over 4 hours every 3 weeks. Good-risk patients received ACM-A at the starting daily dose of 100 mg/m2 while patients who had had therapy with radiation or myelosuppressive drugs such as mitomycin C or a nitrosourea compound received an initial daily dose of 80 mg/m2. There were no complete or partial remissions in this study. Twelve of 30 evaluable patients had disease stabilization. Nausea and vomiting were the dose-limiting toxic effects; myelosuppression was moderate, with neutropenia more severe than thrombocytopenia. Other toxic effects included diarrhea (in 53% of the treatment courses), phlebitis (36%), and mucositis (27%). Alopecia was rare and occurred in 3% of treatment courses, while none of the patients developed clinical manifestation of cardiac toxicity. Aclacinomycin-A administered by the single-dose schedule as used in this study is not effective against colorectal cancer.

Topics: Aclarubicin; Adult; Aged; Antibiotics, Antineoplastic; Colonic Neoplasms; Drug Evaluation; Female; Humans; Male; Middle Aged; Naphthacenes; Nausea; Neoplasm Metastasis; Neutropenia; Rectal Neoplasms; Thrombocytopenia