aclarubicin and Leukemia-P388

A new dosage formulation (ACR-CH), composed of aclarubicin (ACR) bound to fine activated carbon particles, was developed for the treatment of lymph node metastases in patients with breast cancer. In a mice experimental model, ACR-CH had superior therapeutic effects on lymph node metastases compared to the same dose of ACR aqueous solution. In clinical trials, patients with breast cancer received a local injection of 10 mg/person of ACR in the form of ACR-CH or ACR aqueous solution just before mastectomy. In the regional lymph nodes removed by the operation, the ACR concentration of 40.7 micrograms/g in patients given ACR-CH was higher than the 25.1 micrograms/g in patients given ACR aqueous solution, whereas in blood plasma the concentration was higher in patients given ACR aqueous solution than in those given ACR-CH.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Carbon; Combined Modality Therapy; Delayed-Action Preparations; Female; Humans; Leukemia P388; Lymphatic Metastasis; Mastectomy; Mice

F 11782 (2",3"-bis pentafluorophenoxyacetyl-4",6"-ethylidene-beta-D-glucoside of 4'-phosphate-4'-dimethylepipodophyllotoxin, di-N-methyl glucamine salt) is a newly synthesized dual catalytic inhibitor of topoisomerases I and II with major in vivo antitumour activity. In this study, we compared and contrasted F 11782 with three other known inhibitors of both these nuclear enzymes, namely aclarubicin. intoplicin and TAS-103, and established its novel mechanism of action.. In vitro growth-inhibitory effects against a panel of murine and tumour cell lines were measured by cell counting, clonogenicity or tetrazolium metabolic dye (MTT) assays. In vivo antitumour activities were evaluated against two murine tumour models (i.v. P388 leukaemia and s.c. B16 melanoma). Finally, interactions with either DNA or DNA-topoisomerases were determined using various methodologies: DNA-intercalator displacement, pBR322 DNA relaxation, kDNA decatenation, topoisomerase II extractability measurements, stabilization of topoisomerase-induced cleavable complexes (CC) in vitro and in cells, and gel retardation assays.. F 11782 had a different profile of sensitivities and proved generally less cytotoxic than the other dual inhibitors tested in vitro, while showing significantly superior antitumour activity in vivo. F 11782, which did not stabilize CC either in vitro or in cells, was the only compound of this series capable of inhibiting the catalytic activity of both DNA-topoisomerases without interacting with DNA, and of completely impairing the binding of these nuclear proteins to DNA. Moreover, only cotreatment of cells in vitro with F 11782 enhanced the cytotoxic activity of etoposide.. These results emphasize the novel mechanism of action of F 11782 vis-a-vis the other dual inhibitors of topoisomerases I and II and so augur well for its future clinical development.

Topics: Aclarubicin; Aminoquinolines; Animals; Antineoplastic Agents; Cell Division; Enzyme Inhibitors; Etoposide; Humans; Indenes; Indoles; Leukemia L1210; Leukemia P388; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Naphthalenes; Pyrans; Pyridines; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Tumor Cells, Cultured; Urinary Bladder Neoplasms

It has been reported that aclarubicin inhibits etoposide (VP-16) induced cytotoxicity in human lung cancer cell lines (1, 2). However, it still remains unclear how aclarubicin (ACR) inhibits etoposide-induced cytotoxicity. We report here that the combination of ACR and VP-16 showed antagonistic cytotoxic effect in P388 murine leukemic cells. DNA unwinding assay showed that 1000 ng/ml ACR significantly reduced VP-16 induced early DNA double strand(ds) breaks compared to that of VP-16 alone at a concentration of 10 microM. However, ACR did not inhibit VP-16 induced early DNA double strand breaks at a concentration of 100 ng/ml, a clinically achievable concentration. Furthermore, DNA repair occurred within two hours after removing VP-16 even if ACR was co-cultured at concentrations of 100 and 1000 ng/ml. DNA agarose gel electrophoresis and detection of sub-G1 fraction by flowcytometer showed that 100 ng/ml of ACR inhibited VP-16 induced DNA ladder formation and formation of sub-G1 fraction. Radioactive precursor incorporation studies showed that VP-16 inhibited DNA synthesis rather than RNA synthesis. On the other hand, ACR selectively inhibited RNA synthesis at a concentration of 100 ng/ml. The VP-16 induced increment of [3H]-L-leucine uptake was canceled by addition of 100 ng/ml of ACR. These data suggest that ACR inhibited VP-16 induced apoptosis by the inhibition of RNA synthesis along with protein synthesis, but not early DNA double strand breaks and DNA repair at a concentration of 100 ng/ml in P388 murine leukemic cells.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Apoptosis; DNA Damage; DNA, Neoplasm; Drug Interactions; Etoposide; Flow Cytometry; G1 Phase; Leukemia P388; Mice; Neoplasm Proteins; Nucleic Acid Synthesis Inhibitors; RNA, Neoplasm; Tumor Cells, Cultured

Aclacinomycin (ACR) is an anthracycline anticancer drug that shows marked effects in Adriamycin (ADM)-resistant tumors. ADM, however, is not effective against ACR-resistant tumor cells. When tumor cells acquire resistance to ACR, though the resistance is not easily acquired, they show strong cross-resistance to ADM. To study the mechanism underlying these phenomena, we studied the resistance mechanism of ACR- and ADM-resistant P388 leukemia cells. The P388/ACR cells showed 4.9- and 100-fold resistance to ACR and ADM, respectively, whereas the P388/ADM cells showed respectively 2.0- and 270-fold resistance. Both P388/ACR and P388/ADM cells expressed large amounts of P-glycoprotein, and the amount was 3-fold higher in the P388/ACR than in the P388/ADM cells. As a result, the accumulation of vincristine and ADM were greatly reduced in P388/ACR and P388/ADM cells, as compared with the parental P388 cells. The accumulation of ACR, however, was moderately reduced in both the resistant cell lines. ACR accumulation in P388/ACR and P388/ADM cells was reduced to respectively 37 and 64% of the level in P388 cells. The amount and the activity of topoisomerase II were comparable in P388 and P388/ACR cells, but they were reduced in P388/ADM cells. Consequently, the formation of protein (topoisomerase II)-DNA cross-links induced by a topoisomerase II inhibitor was more prominent in the P388 and P388/ACR nuclei than in the P388/ADM nuclei. Notably, ACR could reduce the protein-DNA cross-links equally in the nuclei of P388, P388/ACR, and P388/ADM cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Nucleus; DNA Topoisomerases, Type II; DNA, Neoplasm; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Humans; Immunoblotting; Leukemia P388; Tumor Cells, Cultured; Verapamil; Vincristine

Seven days after a subcutaneous inoculation of 5 x 10(5) P388 leukemia cells into the foot pad of the left hind paw of donor mouse, aclarubicin (0.2 mg/kg body weight) was injected subcutaneously into the hind paw of the opposite foot pad in the form of ACR-CH or aclarubicin aqueous solution. On day 10, the left popliteal and the lower para-aortic lymph nodes taken from each donor were transferred intraperitoneally to a normal recipient mouse. The combined survival time of recipients and the viable P388 leukemia cell number in popliteal and para-aortic lymph nodes were estimated with a calibration formula. Our results showed that the survival curve of recipients given ACR-CH was statistically improved compared with that of other treatment groups.

Topics: Aclarubicin; Animals; Charcoal; Leukemia P388; Lymph Nodes; Lymphatic Metastasis; Male; Mice; Mice, Inbred Strains

Seven days after a subcutaneous inoculation of 5 x 10(5) P388 leukemia cells into the foot pad of the left hind paw of donor mouse, aclarubicin (0.2mg/kg body weight) was injected subcutaneously into the hind paw of the opposite foot pad in the form of ACR-CH or aclarubicin aqueous solution. On day 10, the left popliteal and the lower para-aortic lymph nodes taken from each donor were transferred intraperitoneally to a normal recipient mouse. The combined survival time of recipients and the viable P388 leukemia cell number in popliteal and para-aortic lymph nodes were estimated with a calibration formula. Our results showed that the survival curve of recipients given ACR-CH was statistically improved compared with that of other treatment groups.

Topics: Aclarubicin; Animals; Carbon; Drug Delivery Systems; Leukemia P388; Lymphatic Metastasis; Mice; Povidone

The anti-cancer drug aclarubicin (2.0 mg/kg body weight) was injected into the left popliteal lymph node (the primary draining node of the foot-pad region) or into the tail vein, 8 days after a subcutaneous inoculation of 5 x 10(5) P388 leukemia cells/mouse in the left hind paw foot-pad of mouse (donor). During this time, metastases were established in the lower para-aortic nodes (the secondary draining nodes of this region). On day 10, the lower para-aortic nodes taken from each donor were transferred intraperitoneally to a normal mouse (recipient). From the recipients' survival time, the viable P388 leukemia cell number in the para-aortic nodes per donor mouse was estimated with a calibration line. The recipients' survival curve in the intralymphatic chemotherapy group was statistically significantly better than that in the intravenous chemotherapy group.

Topics: Aclarubicin; Animals; Antineoplastic Agents; Calibration; Disease Models, Animal; Female; Injections, Intralymphatic; Leukemia P388; Lymphatic Metastasis; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Tumor Cells, Cultured

Study on antitumor activity of free and liposomal anthracycline antibiotic aclarubicin in vitro and in vivo showed that liposomal aclarubicin was characterised by activity against ascitic Ehrlich carcinoma comparable to that of free aclarubicin when used in a dose of 25 mg/kg. Liposomal antibiotic had a more pronounced antimetastatic action and showed no toxicity (in a dose of 30 mg/kg). Liposomal aclarubicin had a higher activating capacity with respect to the macrophage tumoricidal properties.

Topics: Aclarubicin; Animals; Carcinoma, Ehrlich Tumor; Drug Carriers; Drug Screening Assays, Antitumor; Emulsions; Lethal Dose 50; Leukemia P388; Liposomes; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis

Aclarubicin (ACR) has a selective inhibitory effect on the synthesis of RNA in the cells. The time of the antibiotic contact with the cells is an important factor in realization of its cytotoxic activity. As compared to adriamycin, ACR has a low specific activity in lymphoid leukemia P388, melanoma B16 and lung cancer LL. The therapeutic efficacy of ACR depended on the scheme of its use: in treatment of rapidly proliferating tumors such as P388 the highest effect is attained with the daily use of the antibiotic for 9 days, in treatment of slowly developing melanoma B16 the results were more satisfactory with intermittent use of the drug on days 1, 5 and 9 after the strain transplantation. The new antibiotic was highly effective on its use either intravenously or orally.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Cells, Cultured; DNA, Neoplasm; Doxorubicin; Drug Evaluation, Preclinical; Female; In Vitro Techniques; Lethal Dose 50; Leukemia P388; Male; Mice; Naphthacenes; Neoplasm Transplantation; Neoplasms, Experimental; Time Factors