Therapy with transcutaneous administration of imiquimod combined with oral administration of sorafenib suppresses renal cell carcinoma growing in an orthotopic mouse model

Karashima,Takashi; Udaka,Keiko; Niimura,Mayumi; Suzuki,Katsuhide; Osakabe,Hiroto; Shimamoto,Tsutomu; Fukata,Satoshi; Inoue,Keiji; Kuroda,Naoto; Seiki,Motoharu; Shuin,Taro

doi:10.3892/ol.2017.6235

Therapy with transcutaneous administration of imiquimod combined with oral administration of sorafenib suppresses renal cell carcinoma growing in an orthotopic mouse model

Authors:
- Takashi Karashima
- Keiko Udaka
- Mayumi Niimura
- Katsuhide Suzuki
- Hiroto Osakabe
- Tsutomu Shimamoto
- Satoshi Fukata
- Keiji Inoue
- Naoto Kuroda
- Motoharu Seiki
- Taro Shuin
View Affiliations

Affiliations: Department of Urology, Kōchi Medical School, Nankoku, Kōchi 783‑8505, Japan, Department of Immunology, Kōchi Medical School, Nankoku, Kōchi 783‑8505, Japan, Department of Diagnostic Pathology, Kōchi Red Cross Hospital, Kōchi, Kōchi 780‑0062, Japan, Medical Innovation Center, Kōchi Medical School, Nankoku, Kōchi 783‑8505, Japan
Published online on: May 24, 2017 https://doi.org/10.3892/ol.2017.6235
Pages: 1162-1166

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Imiquimod is an imidazoquinoline immune response modifier that is used in antiviral and antiallergic creams. Combination therapy using transcutaneous imiquimod and oral sorafenib was previously demonstrated to reduce the tumor burden of renal cell carcinoma growing cutaneously in a mouse model. In the present study, an orthotopic mouse model was used to investigate whether combined treatment with oral sorafenib and transcutaneous imiquimod inhibited renal cell carcinoma growing in the kidney. Kidneys of female BALB/c mice were orthotopically implanted with RENCA mouse kidney cancer cells, and the mice were transcutaneously treated with cream containing imiquimod and/or with orally administered sorafenib 5 days following cell implantation. Tumor burden and incidence were determined 28 days following the start of therapy. Splenocyte activity was quantified using the 51Cr release assay and the fluorescence‑activated cell sorting assay with cluster of differentiation (CD) 4 and CD8 antibodies. Imiquimod, sorafenib and combination therapy were tolerated well. A combination of transcutaneous imiquimod and oral sorafenib inhibited the growth of RENCA tumors in the kidney significantly compared with the control. The 51Cr release assay demonstrated that transcutaneous imiquimod therapy significantly induced the release of 51Cr from RENCA cells compared with the control. The fluorescence‑activated cell sorting assay demonstrated that transcutaneous imiquimod therapy induced CD8+ and CD4‑ splenocytes compared with the control. In summary, the results of the present study demonstrated that combined treatment with transcutaneous imiquimod and oral sorafenib may be a promising strategy for the treatment of patients with renal cell carcinoma.

View Figures

View References

1	Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 366:2443–2454. 2012. View Article : Google Scholar : PubMed/NCBI
2	Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 366:2455–2465. 2012. View Article : Google Scholar : PubMed/NCBI
3	Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Sherry RM, Topalian SL, Yang JC, Lowy I and Rosenberg SA: Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 33:828–833. 2010. View Article : Google Scholar : PubMed/NCBI
4	Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K and Akira S: Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 3:196–200. 2002. View Article : Google Scholar : PubMed/NCBI
5	Peet NP, Baugh LE, Sunder S and Lewis JE: Synthesis and antiallergic activity of some quinolinones and imidazoquinolinones. J Med Chem. 28:298–302. 1985. View Article : Google Scholar : PubMed/NCBI
6	Lebwohl M, Dinehart S, Whiting D, Lee PK, Tawfik N, Jorizzo J, Lee JH and Fox TL: Imiquimod 5% cream for the treatment of actinic keratosis: Results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol. 50:714–721. 2004. View Article : Google Scholar : PubMed/NCBI
7	Geisse JK, Rich P, Pandya A, Gross K, Andres K, Ginkel A and Owens M: Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: A double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol. 47:390–398. 2002. View Article : Google Scholar : PubMed/NCBI
8	Naylor MF, Crowson N, Kuwahara R, Teague K, Garcia C, Mackinnis C, Haque R, Odom C, Jankey C and Cornelison RL: Treatment of lentigo maligna with topical imiquimod. Br J Dermatol. 149 Suppl 66:S66–S70. 2003. View Article : Google Scholar
9	Lyons JF, Wilhelm S, Hibner B and Bollag G: Discovery of a novel Raf kinase inhibitor. Endocr Relat Cancer. 8:219–225. 2001. View Article : Google Scholar : PubMed/NCBI
10	Karashima T, Komatsu T, Niimura M, Kawada C, Kamada M, Inoue K, Udaka K, Kuroda N and Shuin T: Novel combination therapy with imiquimod and sorafenib for renal cell carcinoma. Int J Urol. 21:702–706. 2014. View Article : Google Scholar : PubMed/NCBI
11	Vines T and Faunce T: Freedom of information applications as an ‘evergreening’ tactic: Secretary, department of health and ageing v iNOVA pharmaceuticals (Australia) Pty Ltd (2010) 191 FCR 573; [2010]FCA 1442. J Law Med. 19:43–52. 2011.PubMed/NCBI
12	Karashima T, Inoue K, Fukata S, Iiyama T, Kurabayashi A, Kawada C and Shuin T: Blockade of the vascular endothelial growth factor-receptor 2 pathway inhibits the growth of human renal cell carcinoma, RBM1-IT4, in the kidney but not in the bone of nude mice. Int J Oncol. 30:937–945. 2007.PubMed/NCBI
13	Visseren MJ, van Elsas A, van er Voort EI, Ressing ME, Kast WM, Schrier PI and Melief CJ: CTL specific for the tyrosinase autoantigen can be induced from healthy donor blood to lyse melanoma cells. J Immunol. 154:3991–3998. 1995.PubMed/NCBI
14	Li Z, Oka Y, Tsuboi A, Fujiki F, Harada Y, Nakajima H, Masuda T, Fukuda Y, Kawakatsu M, Morimoto S, et al: Identification of a WT1 protein-derived peptide, WT1, as a HLA-A 0206-restricted, WT1-specific CTL epitope. Microbiol Immunol. 52:551–558. 2008. View Article : Google Scholar : PubMed/NCBI
15	Majewski S, Marczak M, Mlynarczyk B, Benninghoff B and Jablonska S: Imiquimod is a strong inhibitor of tumor cell-induced angiogenesis. Int J Dermatol. 44:14–19. 2005. View Article : Google Scholar : PubMed/NCBI
16	Vidal D, Matías-Guiu X and Alomar A: Efficacy of imiquimod for the expression of Bcl-2, Ki67, p53 and basal cell carcinoma apoptosis. Br J Dermatol. 151:656–662. 2004. View Article : Google Scholar : PubMed/NCBI
17	Kim CH, Ahn JH, Kang SU, Hwang HS, Lee MH, Pyun JH and Kang HY: Imiquimod induces apoptosis of human melanocytes. Arch Dermatol Res. 302:301–306. 2010. View Article : Google Scholar : PubMed/NCBI
18	Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 356:125–134. 2007. View Article : Google Scholar : PubMed/NCBI
19	Santoni M, Berardi R, Amantini C, Burattini L, Santini D, Santoni G and Cascinu S: Role of natural and adaptive immunity in renal cell carcinoma response to VEGFR-TKIs and mTOR inhibitor. Int J Cancer. 134:2772–2777. 2014. View Article : Google Scholar : PubMed/NCBI
20	Cabrera R, Ararat M, Xu Y, Brusko T, Wasserfall C, Atkinson MA, Chang LJ, Liu C and Nelson DR: Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 62:737–746. 2013. View Article : Google Scholar : PubMed/NCBI
21	Delgado-Charro MB and Guy RH: Transdermal Drug DeliveryHillary AM, Lloyd AW and Swarbrick J: Drug Delivery and Targeting: For Pharmacists and Pharmaceutical Scientists. Taylor & Francis; London and New York: pp. 189–214. 2001
22	Mathias NR and Hussain MA: Non-invasive systemic drug delivery: Developability considerations for alternate routes of administration. J Pharm Sci. 99:1–20. 2010. View Article : Google Scholar : PubMed/NCBI
23	Oertel W, Ross JS, Eggert K and Adler G: Rationale for transdermal drug administration in Alzheimer disease. Neurology. 69 4 Suppl 1:S4–S9. 2007. View Article : Google Scholar : PubMed/NCBI
24	Seeberger LC and Hauser RA: Optimizing bioavailability in the treatment of Parkinson's disease. Neuropharmacol. 53:791–800. 2007. View Article : Google Scholar
25	Santini B, Zanoni I, Marzi R, Cigni C, Bedoni M, Gramatica F, Palugan L, Corsi F, Granucci F and Colombo M: Cream formulation impact on topical administration of engineered colloidal nanoparticles. PLoS One. 10:e01263662015. View Article : Google Scholar : PubMed/NCBI
26	Soria I, Myhre P, Horton V, Ellefson P, McCarville S, Schmitt K and Owens M: Effect of food on the pharmacokinetics and bioavailability of oral imiquimod relative to a subcutaneous dose. Int J Clin Pharmacol Ther. 38:476–481. 2000. View Article : Google Scholar : PubMed/NCBI
27	Stein P, Gogoll K, Tenzer S, Schild H, Stevanovic S, Langguth P and Radsak MP: Efficacy of imiquimod-based transcutaneous immunization using a nano-dispersed emulsion gel formulation. PLoS One. 9:e1026642014. View Article : Google Scholar : PubMed/NCBI