The introduction of all-trans retinoic acid in 1985 combined with anthracycline-based chemotherapy has revolutionized the prognosis of acute promyelocytic leukemia (APL) with current complete response rates of more than 90% and cure rates of approximately 80%. The subsequent advent of arsenic trioxide in 1994 marked an additional milestone in APL treatment and has inspired the design of rationally targeted, chemotherapy-free front-line treatment regimens without compromising the excellent outcome achieved by anthracycline-containing protocols. APL is, therefore, a unique subtype of acute myeloid leukemia potentially curable with targeted therapies without any exposure to conventional DNA-damaging chemotherapy. Cure rates of APL can be further increased by implementing management strategies to reduce early hemorrhagic deaths, which remain the major cause of treatment failure with the current therapy.
"Arsenic trioxide was used as a model agent here based on the reports that is causes acute vascular shutdown in solid tumors , . Moreover, ATO (TRISENOX®) is FDA approved in the United States for treatment of relapsed and refractory acute promyelocytic leukemia (APL) patients ,  and there are ongoing clinical trials for solid tumors including liver, brain, lung and breast cancers (ClinicalTrials.gov). Dose limiting toxicity has been widely reported to limit potential use of ATO, but new targeted formulations have been presented , . "
[Show abstract][Hide abstract] ABSTRACT: Small animal imaging provides diverse methods for evaluating tumor growth and acute response to therapy. This study compared the utility of non-invasive optical and ultrasound imaging to monitor growth of three diverse human tumor xenografts (brain U87-luc-mCherry, mammary MCF7-luc-mCherry, and prostate PC3-luc) growing in nude mice. Bioluminescence imaging (BLI), fluorescence imaging (FLI), and Power Doppler ultrasound (PD US) were then applied to examine acute vascular disruption following administration of arsenic trioxide (ATO).
During initial tumor growth, strong correlations were found between manual caliper measured tumor volume and FLI intensity, BLI intensity following luciferin injection, and traditional B-mode US. Administration of ATO to established U87 tumors caused significant vascular shutdown within 2 hrs at all doses in the range 5 to 10 mg/kg in a dose dependant manner, as revealed by depressed bioluminescent light emission. At lower doses substantial recovery was seen within 4 hrs. At 8 mg/kg there was >85% reduction in tumor vascular perfusion, which remained depressed after 6 hrs, but showed some recovery after 24 hrs. Similar response was observed in MCF7 and PC3 tumors. Dynamic BLI and PD US each showed similar duration and percent reductions in tumor blood flow, but FLI showed no significant changes during the first 24 hrs.
The results provide further evidence for comparable utility of optical and ultrasound imaging for monitoring tumor growth, More specifically, they confirm the utility of BLI and ultrasound imaging as facile assays of the vascular disruption in solid tumors based on ATO as a model agent.
PLoS ONE 09/2012; 7(9):e46106. DOI:10.1371/journal.pone.0046106 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The introduction of all-trans retinoic acid to anthracycline-based chemotherapy has revolutionized the prognosis of patients with acute promyelocytic leukemia (APL). The introduction of arsenic trioxide enabled the therapeutic approach of rationally targeted frontline protocols with minimal or no traditional cytotoxic chemotherapy and without compromise of previously established outstanding outcomes with anthracycline-based regimens. Although most of the current investigative efforts in APL are focused on developing potentially curative therapy without the exposure to toxicities and risks of DNA-disrupting agents, the cure rate can further be increased by implementing meticulous supportive care strategies that counter early coagulopathy-related deaths.
Hematology/oncology clinics of North America 12/2011; 25(6):1215-33, viii. DOI:10.1016/j.hoc.2011.10.002 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteosarcoma (OS) is one of the most common malignant bone tumors. Despite the advancement of diagnosis and treatment for OS, the prognosis remains poor. We investigated the proliferation inhibitory effect of all-trans retinoic acid (ATRA) for human OS and the possible mechanism underlying this effect. We examined the proliferation inhibition and apoptosis-inducing effects of ATRA in 143B OS cells. We validated this effect by exogenously expressing the retinoic acid receptor alpha (RARα) in 143B OS cells and injecting the cells into nude mice. We explored the possible mechanism for the proliferation inhibitory effect of ATRA on OS cells and multipotential progenitor cells by detecting osteogenic markers. We demonstrated that the endogenous retinoic acid receptor and retinoid X receptor are all detectable in the commercially available OS cell lines and in primary osteosarcoma cells. ATRA inhibits the proliferation of OS cells in a concentration-dependent manner, as well as induces apoptosis in 143B OS cells. The exogenous expression of RARα inhibits the tumor growth and cell proliferation in vivo. The alkaline phosphatase activity, protein levels of osteopontin (OPN) and osteocalcin (OCN) are all promoted by ATRA in OS cells and mouse embryonic fibroblasts (MEFs), at least by activating the Smad signaling pathway. Collectively, our results strongly indicate that ATRA can inhibit the tumor growth of OS by promoting osteogenic differentiation in OS cells, which is mediated in part by activating Smad signaling. Therefore, combination of ATRA with other current chemotherapy agents may be a promising therapy strategy for OS treatment.
International Journal of Oncology 04/2012; 41(1):153-60. DOI:10.3892/ijo.2012.1426 · 3.03 Impact Factor
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