Disease relevance of ICRF 186

• Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity [1].
• Antitumor response rates were similar (FDC vs. FDC + ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression) [1].
• Although myelosuppression was slightly greater in the FDC + ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups [1].
• Control dogs received 0.9% NaCl solution i.v. 30 min after ICRF-187 i.p. (12.5 mg/kg body weight) [2].
• Role of (+-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) in modulating free radical scavenging enzymes in doxorubicin-induced cardiomyopathy [3].

High impact information on ICRF 186

• We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions [1].
• Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187 [4].
• Bisdioxopiperazine drugs such as ICRF-187 are catalytic inhibitors of DNA topoisomerase II, with at least two effects on the enzyme: namely, locking it in a closed-clamp form and inhibiting its ATPase activity [5].
• Human small cell lung cancer NYH cells selected for resistance to ICRF-187 (NYH/187) showed a 25% increase in topoisomerase IIalpha level and no change in expression of the beta isoform [5].
• Western blots of topoisomerase IIalpha after incubation of CHO cells with ICRF-187 demonstrated a marked band depletion, whereas this effect was completely lacking in CHO/159-1 cells, and an equal effect of VP-16 was observed in both lines [6].

Chemical compound and disease context of ICRF 186

• The postulated mechanism of cardioprotection is metal chelation, because ICRF-187 did not alter the toxicity of a nonchelating mitoxantrone analogue [7].
• The bisdioxopiperazine compound ICRF-187 (ADR-529) specifically abrogates this toxicity both in preclinical animal models and in humans [8].
• To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCL nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin [9].
• Effects of ICRF-187 on the cardiac and renal toxicity of epirubicin in spontaneously hypertensive rats [10].
• Morphologic and morphometric evaluation of the effect of ICRF-187 on bleomycin-induced pulmonary toxicity [11].

Biological context of ICRF 186

• We studied the effects of ICRF-187 and ICRF-159 on the progression of cultured epithelial cells through M phase [12].
• Cell cycle progression and chromosome segregation in mammalian cells cultured in the presence of the topoisomerase II inhibitors ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane; ADR-529] and ICRF-159 (Razoxane) [12].
• Lipid peroxidation and CaATPase inactivation catalyzed by Fe3+, Fe3+ ADP, or Fe3(+)-ferritin were substantially inhibited by ICRF-198 but only partially inhibited by ICRF-187 [13].
• Immunolabeling with Crest autoimmune sera, which recognizes centromere proteins, and with MPM-2 monoclonal antibody, which recognizes mitotic phosphoproteins, indicated that the centromeres of the chromosomes assembled a normal metaphase array in the presence of ICRF-187 and ICRF-159 [12].
• Inhibition of topoisomerase II activity by ICRF-187 greatly diminishes UVA-induced DNA breakage, implying topoisomerase IIalpha and IIbeta as endogenous co-factors modulating and possibly aggravating the impact of UVA light on the genome [14].

Anatomical context of ICRF 186

• Synergistic activity of doxorubicin and the bisdioxopiperazine (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF 187) against the murine sarcoma S180 cell line [15].
• No inhibition of topoisomerase II catalytic activity by ICRF-187 was seen in CHO/159-1 cells up to 500 microM, whereas inhibition was evident at 50 microM in wild-type CHO cells [6].
• Comparable decreases in white blood cell count, red blood cell count, hemoglobin, and serum iron concentration were found in animals receiving doxorubicin with or without ICRF-187 [2].
• ICRF-187 induced myocyte protection which was dependent on the dose and duration of exposure [7].
• The activities of the antioxidants superoxide dismutase, glutathione peroxidase, and catalase and the concentration of reduced glutathione were measured in the heart, liver, kidneys, and skeletal muscle of mice treated with doxorubicin, ICRF-187, or the drug combination [3].

Associations of ICRF 186 with other chemical compounds

• Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05) [16].
• Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model [17].
• Mitoxantrone cardiotoxicity was investigated in isolated neonatal rat heart myocytes treated for 3 h in the presence or absence of the metal chelator ICRF-187 [7].
• For instance, complex-stabilizing Topo II inhibitors such as etoposide, teniposide, and doxorubicin, which cause DNA damage, strongly induce FasL expression; by contrast, non-DNA-damaging catalytic Topo II inhibitors such as ICRF-187 and merbarone do not do this [18].
• Two high-dose etoposide models are described, namely use of the weak base chloroquine in tumors with acidic extracellular pH and targeting of CNS tumors with protection of normal tissue by the bisdioxopiperazine ICRF-187 [19].

Gene context of ICRF 186

• However, the killing caused by ICRF-193 and ICRF-187 is not enhanced by mutations in the RAD52 pathway [20].
• However, BMY 25067-induced OH formation was more sensitive to inhibition by superoxide dismutase (SOD) and the iron chelator ICRF-187 [21].
• Both the arrhythmia and the free radical signal were partially blocked by SOD, catalase and ICRF-187, indicating that iron-dependent oxygen radical formation from BMY-25282 (and possibly other compounds) is involved, in part, in inducing toxic manifestations in the rat heart and possibly in clinic [21].
• Chronic treatment with these drugs or each combined with ICRF-187 did not change the antioxidant levels relative to the control values [17].
• Selection of human leukemic CEM cells for resistance to the DNA topoisomerase II catalytic inhibitor ICRF-187 results in increased levels of topoisomerase IIalpha and altered G(2)/M checkpoint and apoptotic responses [22].

Analytical, diagnostic and therapeutic context of ICRF 186

• Response rates to chemotherapy, event-free and overall survival, and noncardiac toxicities appear to be unaffected by the use of ICRF-187 [23].
• Western blotting after incubation with ICRF-187 showed no depletion of the alpha isoform in NYH/187 cells in contrast to wild-type (wt) cells, whereas equal depletion of the beta isoform was observed in the two sublines [5].
• Additional clinical trials with larger numbers of patients are needed to determine if the short-term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long-term survivors of childhood cancer [23].
• Furthermore, normal morphology of the electron micrographs after treatment with doxorubicin and ICRF-187 indicated that ICRF-187 was cardioprotective [3].
• The catalytic topoisomerase II inhibitor ICRF-187 prevented the effect when added to the cell culture before the UVA pulse but promoted it when added thereafter [14].

References