Pathogenesis of Hand-Foot Syndrome induced by PEG-modified liposomal Doxorubicin
Tóm tắt
PEGL-DOX is an excellent treatment for recurrent ovarian cancer that rarely causes side-effects like cardiotoxicity or hair loss, but frequently results in Hand-Foot Syndrome (HFS). In severe cases, it can become necessary to reduce the PEGL-DOX concentration or the duration of the drug therapy, sometimes making it difficult to continue treatment. In this study, we prepared an animal model to compare the effects of DOX versus PEGL-DOX, and we noticed that only treatment with PEGL-DOX resulted in HFS, which led us to conclude that extravasation due to long-term circulation was one of the causes of HFS. In addition, we were able to show that the primary factor leading to the skin-specific outbreaks in the extremities was the appearance of reactive oxygen species (ROS) due to interactions between DOX and the metallic Cu(II) ions abundant in skin tissue. ROS directly disturb the surrounding tissue and simultaneously induce keratinocyte-specific apoptosis. Keratinocytes express the thermoreceptor TRPM2, which is thought to be able to detect ROS and stimulate the release of chemokines (IL-8, GRO, Fractalkine), which induce directed chemotaxis in neutrophils and other blood cells. Those cells and the keratinocytes then undergo apoptosis and simultaneously release IL-1β, IL-1α, and IL-6, which brings about an inflammatory state. In the future, we plan to develop preventative as well as therapeutic treatments by trapping the ROS.
Tài liệu tham khảo
Zuehle RL. Erythematous eruption of the palms and soles associated with mitotane therapy. Dermatologia. 1974;148:90–2.
Green AE, Peter GR. Pegylated liposomal doxorubicin in ovarian cancer. Int J Nanomed. 2006;1:229–39.
Ministry of Health, Labour and Welfare, Tokyo: The total of the year monthly report of statistics change of the population. 2010.
Sadzuka Y, Tsuruda T, Sonobe T. The characterization and cytotoxicity of mixed PEG-DSG modified liposomes. Yakugaku Zasshi. 2005;125:149–57.
Ihaka R, Gentlemen R. A language for data analysis and graphics. J Comp Graph Stat. 1996;5:299–314.
Asako E. Countermeasure of side effect, a side effect of the anticancer agent treatment, guide of hand-foot syndrome, Chiba cancer center. 2012.
Charrois GJ, Allen TM. Multiple injections of pegylated liposomal doxorubicin: pharmacokinetics and therapeutic activity. J. Pharmacol. Exp. Ther. 2003; 306:1058–67.
Fitzpatrick JE. The cutaneous histopathology of chemotherapeutic reactions. J Cutan Pathol. 1993;20:1–14.
Martschick A, Sehouli J, Patzelt A, et al. The pathogenetic mechanism of anthracycline-induced palmar-plantar erythrodysesthesia. Anticancer Res. 2009;29:2307–14.
Selleri S, Seltmann H, Gariboldi S, et al. Doxorubicin-induced alopecia is associated with sebaceous gland degeneration. J Invest Dermatol. 2006;126:711–20.
Luanpitpong S, Chanvorachote P, Nimmannit U, et al. Mitochondrial superoxide mediates doxorubicin-induced keratinocyte apoptosis through oxidative modification of ERK and Bcl-2 ubiquitination. Biochem Pharmacol. 2012;83:1643–54.
Mizutani H. Mechanism of DNA damage and apoptosis induced by anticancer drugs through generation of reactive oxygen species. Yakugaku Zasshi. 2007;127:1837–42.
Ozawa K. Leakage out of the blood vessel, Series Cancer chemotherapy and Nursing No. 7, In: Ariyoshi Y, Sato R. editors. Cancer chemotherapy and Symptom management No. 4. Tokyo: Kyowa Plan. 2004.
Hiraoka W, Vazquez N, Nieves-Neira W, Chanock SJ, Pommier Y. Role of oxygen radicals generated by NADPH oxidase in apoptosis induced in human leukemia cells. J Clin Invest. 1998;102:1961–8.
Tada-Oikawa S, Oikawa S, Kawanishi M, Yamada M, Kawanishi S. Generation of hydrogen peroxide precedes loss of mitochondrial membrane potential during DNA alkylation-induced apoptosis. FEBS Lett. 1999;442:65–9.
Varbiro G, Veres B, Gallyas F Jr, Sumegi B. Direct effect of Taxol on free radical formation and mitochondrial permeability transition. Free Radic Biol Med. 2001;31:548–58.
Murata M, Suzuki T, Midorikawa K, Oikawa S, Kawanishi S. Oxidative DNA damage induced by a hydroperoxide derivative of cyclophosphamide. Free Radic Biol Med. 2004;37:793–802.
Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem. Pharmacol. 1999; 57:727–41.
Nojima S, Sunamoto J, Inoue K. The Liposome. Tokyo: Nankodo. 1988.
Yamamoto S, Shimizu S, Kiyonaka S, et al. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med. 2008;14:738–47.
Suda T. Molecular mechanism and significance of apoptosis and inflammation with the Fas ligand. Protein Nucleic acid, Enzyme. 1999;44:1478–86.
Suda T. Cell death and medical, immunity. In: Experiment medicine, Chap. 2, vol 19, 2001. pp 198–205.