A magnetite nanoparticle, NPrCAP/M, was produced for intracellular hyperthermia treatment of melanoma by conjugating N-propionyl-cysteaminylphenol (NPrCAP) with magnetite and used for the study of selective targeting and degradation of melanoma cells. NPrCAP/M, like NPrCAP, was integrated as a substrate in the oxidative reaction by mushroom tyrosinase. Melanoma, but not non-melanoma, cells incorporated larger amounts of iron than magnetite from NPrCAP/M. When mice bearing a B16F1 melanoma and a lymphoma on opposite flanks were given NPrCAP/M, iron was observed only in B16F1 melanoma cells and iron particles (NPrCAP/M) were identified within late-stage melanosomes by electron microscopy. When cells were treated with NPrCAP/M or magnetite and heated to 43 degrees C by an external alternating magnetic field (AMF), melanoma cells were degraded 1.7- to 5.4-fold more significantly by NPrCAP/M than by magnetite. Growth of transplanted B16 melanoma was suppressed effectively by NPrCAP/M-mediated hyperthermia, suggesting a clinical application of NPrCAP/M to lesional therapy for melanoma. Finally, melanoma cells treated with NPrCAP/M plus AMF showed little sub-G1 fraction and no caspase 3 activation, suggesting that the NPrCAP/M-mediated hyperthermia induced non-apoptotic cell death. These results suggest that NPrCAP/M may be useful in targeted therapy for melanoma by inducing non-apoptotic cell death after appropriate heating by the AMF.
Melanogenesis substrate, N-propionyl-4-S-cysteaminylphenol (NPr-CAP) is specifically taken up by melanoma cells and inhibits their growth by producing cytotxic free radicals. By taking advantage of this unique chemical agent, we have established melanomatargeting intracellular hyperthermia by conjugating NPrCAP with magnetite nanoparticles (NPrCAP/M) upon exposure to an alternating magnetic field (AMF). This treatment causes cytotoxic reaction as well as heat shock responses, leading to elicitation of antitumor immune response, which was proved by tumor rechallenge test and CTL induction. We found the level of heat shock protein 72 (Hsp72) to be increased in the cell lysate and culture supernatant after intracellular hyperthermia. Melanoma-specific CD8 + T-cell response to dendritic cells loaded with hyperthermiatreated tumor lysate was enhanced when compared with non-treated tumor lysate. When heat shock protein, particularly Hsp72, was immuno-depleted from hyperthermia-treated tumor cell lysate, specific CD8 + T-cell response was abolished. Thus, it is suggested that antitumor immune response induced by hyperthermia using NPrCAP/M is derived from the release of HSP-peptide complex from degraded tumor cells. Therefore, this chemothermo-immuno (CTI)-therapy might be effective not only for primary melanoma but also for distant metastasis because of induction of systemic antimelanoma immune responses. (Cancer Sci 2010; 101: 1939-1946 M elanoma has been increasing in incidence leading to a rise in morbidity and mortality in recent decades. Metastatic melanoma is extremely difficult to cure and continues to have a poor prognosis. Only 12% with metastatic melanoma survive for 5 years.(1) The reason for this poor prognosis is the lack of effective conventional therapies. Various types of therapies such as immunotherapy, chemotherapy, and biologic therapy have been studied in melanoma management. However, a very modest effect was recorded in advanced malignant melanoma. Therefore, there is an emerging need for innovative therapies for the control of advanced melanoma.It has been reported that the intracellular hyperthermia using magnetic nanoparticles is effective for treating certain types of cancer in not only primary but also metastatic lesions.(2-8) Incorporated magnetic nanoparticles generate heat within the cells after exposure to the alternating magnetic field (AMF) due to hysteresis loss or relaxational loss.(9,10) One of us has shown that hyperthermic treatment using magnetite cationic liposomes (MCLs), which are cationic liposomes containing 10-nm magnetite nanoparticles, induces antitumor immunity by enhancement of heat shock protein (HSP) expression. (3,(11)(12)(13) We previously proposed that cross-presentation of extracellular HSP-peptide complex released from hyperthermia-induced necrotic tumor cells is the mechanism for inducing antitumor immunity.(7) In this paper, we present evidence that tumor-derived HSP-peptide complex is responsible for the hyperthermia-mediated antitumor immunity.In addition, ex...
Late onset toxic epidermal necrolysis induced by mogamulizumab, an anti-CC chemokine receptor 4 antibody for the treatment of adult T-cell leukaemia/lymphomaTo the Editor Adult T-cell leukaemia/lymphoma (ATLL) is a rare type of highly aggressive peripheral T-cell malignancy induced by infection with human T-cell leukaemia virus type 1 (HTLV-1) [1]. Acute and lymphoma types of ATLL particularly display an aggressive clinical course with a poor outcome because of the resistance to conventional combination chemotherapies [2]. Mogamulizumab (MOG), a defucosylated humanized monoclonal antibody targeting CC chemokine receptor 4 (CCR4), has recently been launched for treatment of ATLL; almost all ATLL cells express CCR4 [3]. On the other hand, skin rashes have been reported as significant adverse effects of MOG [3]. It is often difficult to distinguish between a skin lesion caused by MOG and an ATLL lesion, and the detail characteristics, clinical course and treatment are still unclear, particularly in severe events including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Here, we report a case of TEN induced by MOG for the treatment of ATLL, which developed at a very late phase after the last infusion of MOG.A 77-year-old man was introduced to our hospital for general fatigue, palpitation and abnormal lymphocytes in peripheral blood. He was diagnosed as having acute type of ATLL by flow cytometry analysis and detection of HTLV-1 antibody. He received low-dose etoposide as an initial treatment; however, lung infiltration of ATLL cells was demonstrated by bronchoalveolar lavage and transbronchial lung biopsy 7 months after diagnosis. Because combination chemotherapies were considered to be a high risk for his general condition, MOG monotherapy was started for 8 months. Detail clinical course of the patient following the treatment of MOG was shown in Figure 1. At the initial infusion of MOG, an infusion reaction was diagnosed for the rapid development of respiratory failure, hyperthermia and systemic skin rash. Three courses of MOG monotherapy were given in combination with a steroid, and MOG was then discontinued owing to a grade 4 adverse effect of thrombocytopenia. He achieved complete remission in both peripheral blood and lung lesions after the therapy. Serum soluble interleukin-2 receptor levels were also significantly decreased from 6290 to 1190 U/ml. On day 5 after the last infusion of MOG, he developed systemic erythema. The skin lesions were improved by administration of 1 mg/kg of prednisolone; however, it was exacerbated again during the tapering of prednisolone. The results of a skin biopsy on day 30 after the last infusion of MOG were consistent with a drug eruption rather than an ATLL lesion. We increased the level prednisolone; however, the lesions continued to progress. On day 42 after the last infusion of MOG, a total of 25% of epidermal necrolysis and erosion, enanthema of the scrotum and systemic symptoms including fever had developed [ Figure 2(A) and (B)], leading to the diagnosis ...
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