Disease relevance of Bisantrene

• Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study [1].
• Congestive heart failure developed in nine patients treated with doxorubicin, zero patients treated with bisantrene, and two patients treated with mitoxantrone [1].
• The present findings suggest that, in addition to direct toxicity to tumor cells, bisantrene may act as a macrophage-activating immunopotentiator [2].
• In this Phase I trial, bisantrene showed clinical antitumor activity against both hematological cancer (i.e., lymphoma and myeloma) and solid tumors (i.e., bladder, lung, and renal cancer and melanoma) [3].
• Immunotherapy of a murine lymphoma by adoptive transfer of syngeneic macrophages activated with bisantrene [4].

High impact information on Bisantrene

• Both pretreatment drug resistance and selective sensitivity (e.g., interferon, bisantrene, methotrexate, vinblastine) at the time of relapse were accurately detected and correlated well with survival duration (p = 0.01 Wilcoxan) [5].
• A human colon carcinoma cell line selected for a 21-fold resistance to mitoxantrone was cross-resistant to the anthracycline, doxorubicin, but not to the anthracene, bisantrene [6].
• Thus, present findings suggest that in addition to a direct cytotoxic effect of bisantrene, the activation of macrophages may contribute to the overall antitumor activity of the drug [4].
• Macrophages prepared from peritoneal exudates of mice treated i.p. with bisantrene were extremely active in inhibiting the growth of tumor cells [2].
• Intravascular precipitation of bisantrene may be responsible for phlebitis and thromboses in humans receiving the drug by i.v. infusion [7].

Chemical compound and disease context of Bisantrene

• Forty-four patients with metastatic breast cancer who had previously received extensive conventional systemic therapy, including combination chemotherapy with doxorubicin, were treated with Bisantrene, a new anthracene derivative [8].
• The investigational antitumor agent bisantrene (9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride) causes frequent local complications of phlebitis and thromboses in patients receiving the drug by peripheral venous infusion [7].
• The relative in vitro toxicities reproduce very well the relative myelosuppression observed in clinical trials with mitoxantrone versus bisantrene but the results were less satisfactory for the comparison of these 2 agents with ametantrone [9].
• The sensitivity of these clonogenic breast tumor cells for mitoxantrone, bisantrene, 4'-epi-doxorubicin, and VP-16 was similar to that for doxorubicin and 5-fluorouracil, but it was less for cis-platinum [10].

Biological context of Bisantrene

• Bisantrene pharmacokinetics was studied in five patients [7].
• In this work, we demonstrate a protective effect conferred by the human multidrug resistance gene (MDR1) to populations of the murine hematopoietic system against the toxic effects of bisantrene, a novel intercalating cytotoxic agent under investigation as an anticancer agent [11].
• While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene required several hours [12].
• The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodium salt 7) at physiological pH [12].
• Mitoxantrone and bisantrene inhibition of platelet aggregation and prostaglandin E2 production in vitro [13].

Anatomical context of Bisantrene

• Of importance, four of the six responses occurred in patients whose therapy was selected on the basis of in vitro sensitivity to bisantrene using the human tumor stem cell assay [3].
• Crystalline inclusions engulfed by lysosomes were found in cells obtained from cultures showing bisantrene precipitates [14].
• One patient with disseminated melanoma had complete disappearance of an axillary node metastasis (for more than 6 months) while developing a brain metastasis, suggesting that bisantrene does not concentrate in the central nervous system [3].
• Immunofluorescence studies with cell lineage-specific monoclonal antibodies showed that bisantrene was specifically toxic for B lymphocytes and macrophages [11].
• A series of 21 new compounds related to bisantrene was synthesized and tested in vitro by using clonogenic assays against a variety of human tumor cell lines, fresh human tumors, and P-388 leukemia [15].

Associations of Bisantrene with other chemical compounds

• Activation of tumor-cytostatic macrophages with the antitumor agent 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazole-2-yl)hydrazone] dihydrochloride (bisantrene) [2].
• Bisantrene (1 mg/ml) in 5% dextrose readily precipitated in the mouse peritoneum [16].
• Using this new method our assay sensitivity has improved to less than 10 ng/ml for bisantrene and 1 ng/ml for mitoxantrone, allowing us to document a prolonged terminal phase plasma half-life for both bisantrene and mitoxantrone [17].
• We studied the clinical pharmacokinetics of the anthracene derivative bisantrene using high-performance liquid chromatographic analysis [18].
• Targeting of anticancer drugs to specific organs by directed intravascular precipitation was studied in calves using 9-10 anthracenedicarboxyaldehyde bis [(4,5-dihydro-lH-imidazol-2-yl) hydrazone] dihydrochloride (Bisantrene), a clinically active anticancer drug with limited solubility at physiological pH [19].

Gene context of Bisantrene

• Retroviral transfer of the human MDR1 gene confers resistance to bisantrene-specific hematotoxicity [11].
• In vitro, MDR1-expressing cell lines are highly cross-resistant to bisantrene, and low levels of P-glycoprotein (the MDR1 gene product cell surface protein) confer resistance to the drug [11].
• In vitro human tumor clonogenic assay showed that the biological activity of bisantrene decreased greater than 4-fold when the drug was incubated with S9 preparations in the presence of NADPH and O2, indicating that the transformation process leads to relatively inactive bisantrene metabolites [20].
• P-glycoprotein mediates profound resistance to bisantrene [21].
• Phase II trial of bisantrene in hepatocellular carcinoma: a Southwest Oncology Group Study [22].

Analytical, diagnostic and therapeutic context of Bisantrene

• We believe that Bisantrene may ultimately have a major role in the effective treatment of metastatic breast cancer, and further clinical trials are warranted [8].
• The influence of bisantrene on T-47D human breast tumor cells was assessed by colony-forming assay in soft agar and by light, fluorescence, and electron microscopy [14].
• Bisantrene might be useful for gene therapy as an in vivo selective agent for cells transduced with MDR1 vectors that also coexpress therapeutic genes of interest [11].
• The relative DNA binding strengths of bisantrene and nine new analogues were measured by spectrophotometric titration and melt transition temperature (Tm) techniques [23].
• A sensitive (detection limit of 2 ng/ml) and specific HPLC method was developed to quantitate bisantrene in patient's plasma and urine [24].

References