Activity of Ruboxyl, a Nitroxyl Derivative of Daunorubicin, on Experimental Models of Colorectal Cancer Metastases

Abstract

We evaluated the activity of ruboxyl (Rbx), a nitroxyl analogue of daunorubicin (Dauno), in experimental models of hepatic metastases from colorectal carcinoma (CRC) and compared it with its parent compound and with 5-fluorouracil (5FU). In mice treated by intraperitoneal injections Rbx and 5FU proved more effective than Dauno: the Index of Inhibition of Metastases in comparison with controls was 43% for Dauno, 70% for 5FU and 84% for Rbx. In BDIX rats implanted with the syngeneic cell line DHD K12/TRb, both Rbx and 5FU, administered as a continuous intravenous infusion for 7 days, reduced the development of liver metastases from a median of 23.8 ± 2.16 for controls to 3.2 ± 1.3 for 5FU and 1.0 ± 1.4 for Rbx (p < 0.0001 versus controls for both treatments): the comparison of Rbx and 5FU showed a trend in favour of this new anthracycline. Median survival was prolonged from 40.6 ± 3.4 days in controls to 56.0 ± 5.8 days with Rbx and 58.0 ± 4.69 days with 5FU. Considering that in a phase I study Rbx showed only minor and manageable toxic side effect, its activity in the clinical treatment of CRC metastases may deserve further attention.

Characterization of azoxymethane-induced colon tumor metastasis to lung in a mouse model relevant to human sporadic colorectal cancer and evaluation of grape seed extract efficacy

“…Another orthotopic hepatic model involves laparotomy to inject SW480 human CRC cells into the cecum of the animal that results in liver tumor formation after 8 weeks (Ding et al, 2011). Furthermore, additional orthotopic liver and lung metastasis models also include surgery and injection or implantation of human tissue into immune compromised animals at various tissue sites including colon and rectum, portal vein, intraperitoneal cavity, and the tail vein (Donigan et al, 2010, Ishihara et al, 2010, Naomoto et al, 1987, Sirovich et al, 1999, Sturm et al, 2003). With the above information in mind, all the current pre-clinical models of metastatic CRC progression are costly, technically challenged, time-consuming, and do not represent an in situ model of human CRC metastasis.…”

Activity of a Nitroxylated Analog of Daunorubicin, Ruboxyl, in B-Lymphoproliferative Disorders

“…At present, it is not clear which role RBX may play in hematologic oncology and in the treatment of solid tumors [10, 18]; this compound also deserves a careful evaluation as an immunosuppressive agent. On the grounds of more detailed pharmacologic studies, further investigations could be planned in WD patients at poor prognosis in an earlier stage of disease, to avoid heavy pretreatment immunosuppression, and in patients with other follicular low-grade lymphomas.…”

Nitroxyl as a Potential Theranostic in the Cancer Arena

“…In human MCF-7 cells, the stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl is able to induce cell damage; this may be associated with HNO reactivity (51). Intraperitoneal injections ruboxyl, a HNO analog of daunorubicin, and 5-fluorouracil reduces the development of liver metastases in experimental mouse models of colorectal cancer (138). It has been found that diazeniumdiolate-based HNO-releasing aspirin exhibits enhanced cytotoxicity toward nonsmall cell lung carcinoma cells but not endothelial cells (13), suggesting cancer-specific sensitivity.…”