aclarubicin and Glioma

Traditional glioma chemotherapy with those second-line drugs such as anthracyclines usually failed because they are inaccessible to blood-brain barrier (BBB) in tumor. In our study, we incorporated aclarubicin (ACL) into cationic albumin-conjugated pegylated nanoparticle (CBSA-NP-ACL) to determine its therapeutic potential of rats with intracranially implanted C6 glioma cells. When labeled with fluorescent probe, 6-coumarin, CBSA-NP was shown to accumulate much more in tumor mass than nanoparticle without conjugated CBSA (NP) 1 hr post intravenous injection, as well as better retention after 24 hr. Tumor drug concentration of CBSA-NP-ACL displayed 2.6- and 3.3-fold higher than that of NP-ACL and ACL solution 1 hr post injection, while 2.7 and 6.6-fold higher after 24 hr, respectively. Moreover, using tumor microdialysis sampling, AUC(0-24 hr) of free drug amount in tumor interstitium delivered by CBSA-NP-ACL was about 2.0- and 2.7-fold higher than that of NP-ACL and ACL solutions, respectively. When the tumor rat model was subjected to 4 cycles of 2 mg/kg of ACL in different formulations, a significant increase of median survival time was found in the group of CBSA-NP-ACL compared with that of saline control animals, animals treated with NP-ACL and ACL solution. By terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling, CBSA-NP-ACL can extensively make the tumor cell apoptosis. Histochemical evaluation by periodic acid Shiff staining and biochemical analysis depicted that the incorporation of ACL into CBSA-NP reduced its toxicity to liver, kidney and heart. Besides, CBSA-NP-ACL was not shown to open tight junction evaluated by BBB coculture. It was concluded that CBSA-NP-ACL could have a therapeutic potential for treatment of glioma.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Brain Neoplasms; Drug Carriers; Glioma; Male; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Serum Albumin; Tissue Distribution

The effects of heat and antitumor drugs on malignant brain tumor cell lines were studied. A human glioblastoma cell line (SKMG1) and rat malignant brain tumor cell lines (T9, EB 679 and TR 481) were used in this experiment. Five different modalities of treatment with heat and drugs were used as follows: (Group 1) exposure to heat alone at 42 degrees C for one hour; (Group 2) exposure to antitumor drug alone for one hour (ACNU 2.5 or 5 micrograms/ml, ACR 0.02 micrograms/ml and CDDP 1 microgram/ml); (Group 3) simultaneous exposure to heat at 42 degrees C and drug for one hour; (Group 4) heat at 42 degrees C given first for one hour, followed by one hour exposure to drug one hour later ("preheating"); (Group 5) drug given first for one hour, followed by one hour exposure to heat at 42 degrees C one hour later ("postheating"). After each treatment, the inhibition rate at 4 days was evaluated and compared for each group. A synergistic effect was observed in Group 3. For example, when T9 cells were exposed to ACNU and to heat at 42 degrees C at the same time for one hour, inhibition rate was 78%, while the rates for Group 1 and Group 2 were 7% and 21%, respectively. The cytotoxicity of simultaneous treatment with antitumor drugs (ACNU, ACR and CDDP) and hyperthermia at 42 degrees C was apparently superior to that of other treatment modalities.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line; Cisplatin; Combined Modality Therapy; Glioma; Humans; Hyperthermia, Induced; Naphthacenes; Nimustine; Nitrosourea Compounds; Rats

The effects of the anticancer drugs Nimustine (ACNU), Aclacinomycin A (ACR), Adriamycin (ADM), Bleomycin (BLM), Cisplatin (CDDP), and 5-Fluorouracil (5-FU) on the multicellular spheroid of a chemically-induced 9L rat glioma was studied. The multicellular spheroid in which cells grow in vitro as three-dimensional aggregates represents a biological model, which is intermediate between monolayer cells in vitro and solid tumors. Spheroids were initiated in bacteriological grade petri dishes seeded with 10(6) 9L rat glioma cells, cultured for four days and thereafter transferred and further developed in a spinner flask. Spheroids of 200-400 micron diameter were sorted and exposed for 24 hours to 5-FU and one hour for other drugs. After treatment both cytotoxic effect and growth delay were analyzed. Following disaggregation using collagenase, pronase and DNAase, cytotoxic effect on multicellular spheroids was measured by colony forming assay and were compared with those effects on 9L monolayer culture cells in the exponential growth. For growth delay assay, multicellular spheroids were individually transferred to 16 mm well containing 0.4 ml agarose base and 2 ml culture medium. Spheroid size was measured twice a week and growth curves were drawn. The growth delay was determined as the treated group vs. control differences in time required to a size four times that of the initial volume. For cells both in the monolayer culture and the multicellular spheroid, the dose response curve for ADM, BLM and 5-FU was "biphasic" and that for ACNU, ACR and CDDP "shoulder-threshold" type.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aclarubicin; Animals; Antineoplastic Agents; Brain Neoplasms; Cell Division; Cell Survival; Cells, Cultured; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Glioma; Naphthacenes; Nimustine; Nitrosourea Compounds; Rats; Tumor Stem Cell Assay

The present study shows that a human malignant glioma cell line (U-251 MG) accumulates and degrades low-density lipoprotein (LDL) by a saturable, high-affinity process (Km approximately equal to 5 micrograms/ml). Accumulation and degradation could be enhanced by preincubating the cells in a lipoprotein-deficient medium. The LDL degradation rate was highest when the cells were proliferating rapidly. An aclacinomycin A:LDL complex containing 150 to 450 drug molecules per LDL particle could be obtained by incubating LDL with a large excess of aclacinomycin A at 40 degrees. When the glioma cells were incubated with the aclacinomycin A:LDL complex, cellular drug accumulation was dependent on the LDL receptor activity. There are four reasons for drawing this conclusion. (a) U-251 MG cells with high LDL receptor activity accumulated more drug than U-251 MG cells with low LDL receptor activity. (b) U-251 MG cells accumulated more drug than a mutant fibroblast line (GM 1915) lacking LDL receptor activity. (c) Aclacinomycin A accumulation was increased when U-251 MG cells were incubated in the presence of chloroquine, an agent that inhibits LDL degradation. (d) Aclacinomycin A accumulation was reduced when U-251 MG cells were incubated in the presence of either an excess of native LDL or heparin, which has been demonstrated to inhibit receptor-mediated binding and degradation of LDL. The aclacinomycin A:LDL complex also inhibited growth of the glioma cells. Our results suggest that the glioma cells studied have LDL receptors and that it may be possible to use LDL as a vehicle for lipophilic antineoplastic drugs in order to increase the drug accumulation in tumor cell populations with high LDL receptor activity.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Biological Availability; Cell Division; Chloroquine; Fibroblasts; Glioma; Humans; Lipoproteins, LDL; Naphthacenes; Receptors, Cell Surface; Receptors, LDL