{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:15:25Z","timestamp":1770833725517,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>This paper reports the first case in which a hyperlipidemic retriever (due to hypothyroidism) with a nasal tumor was successfully treated\u2014achieving partial remission\u2014and managed using a metronomic combination of chlorambucil (3.74 mg\/m2, SID) and prednisolone (0.28 mg\/kg, SID) orally for 9 months at a general practice. A 35 kg spayed female golden retriever aged 8 years and 8 months with nosebleeds visited the Bundang New York Animal Hospital in July 2023 after being diagnosed with nasal carcinoma. A protocol of 4 weeks of chemotherapy followed by 1 week of rest was repeated in two cycles and continued metronomically for 9 months without pause after the two cycles. The nasal exudate was significantly reduced. The size of the nasal tumor was monitored using computed tomography (CT) imaging at a referral hospital. Since the first occurrence of epistaxis, 18 months have passed (as of January 2025) and the nasal exudate is barely visible, and the vital signs and weight of the dog remain stable. The size of the nasal tumor significantly decreased after 9 months of chemotherapy completion without moderate side effects, and all the blood work was normalized, including hypercholesteremia. This study demonstrates that, in hyperlipidemic cancer patients, a prednisolone\/chlorambucil metronomic combination which is cost-effective can be an alternative to tyrosine kinase inhibitors such as sorafenib, even when excluding the price. Through a literature review, the author also investigates the effect of the hyperlipidemic state on cancer, focusing on carcinoma and vascular endothelial growth factor (VEGF), as well as the RAS-RAF-MEK pathway, which is a target for tyrosine kinase inhibitors, in order to reveal the molecular mechanism of chlorambucil metronomic chemotherapy. Also, the author investigates the molecular pathway of carcinoma development in human hyperlipidemia patients through single-cell RNA sequence analysis using open public data, and discusses the molecular action of chlorambucil.<\/jats:p>","DOI":"10.3390\/cimb47080660","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T16:09:55Z","timestamp":1755274195000},"page":"660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Partial Remission Without Recurrence in a 9-Year-Old Golden Retriever with Nasal Carcinoma Treated with Prednisolone\/Chlorambucil Metronomic Combination Therapy: A Case Report and Literature Review of Molecular Mechanisms"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1929-7708","authenticated-orcid":false,"given":"Kyuhyung","family":"Choi","sequence":"first","affiliation":[{"name":"Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul 03080, Republic of Korea"},{"name":"Bundang New York Animal Hospital, Seongnam 13637, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"ref_1","first-page":"159","article-title":"Palliative endoscopic debulking treatment of canine nasal carcinoma\u201435 cases (2016 to 2019): A retrospective multicentric study","volume":"66","author":"Bottero","year":"2025","journal-title":"Can. Vet. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/j.1740-8261.1998.tb01637.x","article-title":"An accelerated technique for irradiation of malignant canine nasal and paranasal sinus tumors","volume":"39","author":"Adams","year":"1998","journal-title":"Vet. Radiol. Ultrasound"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2460\/javma.24.10.0642","article-title":"Outcomes associated with local treatment of nasal planum squamous cell carcinoma in dogs: 89 cases (2003\u20132020)","volume":"1","author":"Raleigh","year":"2025","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/j.1939-1676.2001.tb02309.x","article-title":"Retrospective study of orthovoltage radiation therapy for nasal tumors in 42 dogs","volume":"15","author":"Northrup","year":"2001","journal-title":"J. Vet. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1111\/j.1751-0813.2004.tb12151.x","article-title":"Treatment of eight dogs with nasal tumours with alternating doses of doxorubicin and carboplatin in conjunction with oral piroxicam","volume":"82","author":"Langova","year":"2004","journal-title":"Aust. Vet. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"12472","DOI":"10.18632\/oncotarget.2998","article-title":"Classification of current anticancer immunotherapies","volume":"5","author":"Galluzzi","year":"2014","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2165\/00003495-200060001-00003","article-title":"Epidermal growth factor receptor tyrosine kinase inhibitors as anticancer agents","volume":"60","author":"Ciardiello","year":"2000","journal-title":"Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Baguley, B.C. (2002). A brief history of cancer chemotherapy. Anticancer Drug Development, Academic Press.","DOI":"10.1016\/B978-012072651-6\/50002-4"},{"key":"ref_9","unstructured":"Henry, C.J., and Higginbotham, M.L. (2009). Cancer Management in Small Animal Practice-E-Book: Cancer Management in Small Animal Practice-E-Book, Elsevier Health Sciences."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nrclinonc.2010.82","article-title":"Metronomic chemotherapy: New rationale for new directions","volume":"7","author":"Pasquier","year":"2010","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ng, K.W., Beatty, J.A., Tse, M.P., and Giuliano, A. (2022). Nasal Lymphoma with Low Mitotic Index in Three Cats Treated with Chlorambucil and Prednisolone. Vet. Sci., 9.","DOI":"10.3390\/vetsci9090472"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6462","DOI":"10.1038\/onc.2017.247","article-title":"Elevated tumor LDLR expression accelerates LDL cholesterol-mediated breast cancer growth in mouse models of hyperlipidemia","volume":"36","author":"Gallagher","year":"2017","journal-title":"Oncogene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.metabol.2011.06.020","article-title":"The association of diabetes mellitus with liver, colon, lung, and prostate cancer is independent of hypertension, hyperlipidemia, and gout in Taiwanese patients","volume":"61","author":"Lee","year":"2012","journal-title":"Metabolism"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1159\/000088478","article-title":"VEGF as a key mediator of angiogenesis in cancer","volume":"69","author":"Carmeliet","year":"2005","journal-title":"Oncology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1159\/000068621","article-title":"The Ras-Raf-MEK-ERK pathway in the treatment of cancer","volume":"25","author":"Hilger","year":"2002","journal-title":"Oncol. Res. Treat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1111\/vco.12222","article-title":"Retrospective comparison of three doses of metronomic chlorambucil for tolerability and efficacy in dogs with spontaneous cancer","volume":"15","author":"Custead","year":"2017","journal-title":"Vet. Comp. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"217","DOI":"10.5455\/OVJ.2021.v11.i2.5","article-title":"Long-term management of a cat with nasopharyngeal lymphoma by chlorambucil","volume":"11","author":"Takahashi","year":"2021","journal-title":"Open Vet. J."},{"key":"ref_18","first-page":"5618","article-title":"Effect of corticosteroid on the antitumor activity of lymphokine-activated killer cells and interleukin 2 in mice","volume":"46","author":"Papa","year":"1986","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1093\/jnci\/90.2.134","article-title":"Enhancement of 1, 25-dihydroxyvitamin D3-mediated antitumor activity with dexamethasone","volume":"90","author":"Yu","year":"1998","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3109\/10428199609054821","article-title":"Chlorambucil in chronic lymphocytic leukemia: Mechanism of action","volume":"23","author":"Begleiter","year":"1996","journal-title":"Leuk. Lymphoma"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00280-007-0639-9","article-title":"Safety and anti-tumor activity of sorafenib (Nexavar\u00ae) in combination with other anti-cancer agents: A review of clinical trials","volume":"61","author":"Takimoto","year":"2008","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"De Jesus, M., Mohammed, T., Singh, M., Tiu, J.G., and Kim, A.S. (2022). Etiology and management of dyslipidemia in patients with cancer. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.892335"},{"key":"ref_23","first-page":"1949","article-title":"Cholesterol in platelet biogenesis and activation","volume":"127","author":"Wang","year":"2016","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1182\/blood.V60.1.272.272","article-title":"Chlorambucil therapy in hairy cell leukemia: Effects on lipid composition and lymphocyte subpopulations","volume":"60","author":"Krigel","year":"1982","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100779","DOI":"10.1016\/j.tranon.2020.100779","article-title":"Risk of dyslipidemia associated with VEGF\/VEGFR inhibitors: A meta-analysis","volume":"13","author":"Dai","year":"2020","journal-title":"Transl. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000088479","article-title":"VEGF as a therapeutic target in cancer","volume":"69","author":"Ferrara","year":"2005","journal-title":"Oncology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1309\/HW2MYB5TVF4AM0Y4","article-title":"Hypercholesterolemia impairs angiogenesis in patients with breast carcinoma and, therefore, lowers the risk of metastases","volume":"122","author":"Akcali","year":"2004","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1161\/01.ATV.13.3.427","article-title":"Plasma triglyceride and LDL heterogeneity in familial combined hyperlipidemia","volume":"13","author":"Hokanson","year":"1993","journal-title":"Arterioscler. Thromb. J. Vasc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.jacl.2007.10.001","article-title":"LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study\u2014implications for LDL management","volume":"1","author":"Cromwell","year":"2007","journal-title":"J. Clin. Lipidol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/S0008-6363(03)00526-1","article-title":"PKC\/Raf\/MEK\/ERK signaling pathway modulates native-LDL-induced E2F-1 gene expression and endothelial cell proliferation","volume":"59","author":"Pintus","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Revilla, G., Ruiz-Auladell, L., Vallverd\u00fa, N.F., Santamar\u00eda, P., Moral, A., P\u00e9rez, J.I., Li, C., Fuste, V., Lerma, E., and Corcoy, R. (2023). Low-density lipoprotein receptor is a key driver of aggressiveness in thyroid tumor cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311153"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1073\/pnas.87.7.2598","article-title":"Uptake of low density lipoproteins by human leukemic cells in vivo: Relation to plasma lipoprotein levels and possible relevance for selective chemotherapy","volume":"87","author":"Vitols","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.leukres.2005.06.012","article-title":"Cytotoxic effect of a lipophilic alkylating agent after incorporation into low density lipoprotein or emulsions: Studies in human leukemic cells","volume":"30","author":"Masquelier","year":"2006","journal-title":"Leuk. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12944-019-1075-7","article-title":"Emerging roles of low-density lipoprotein in the development and treatment of breast cancer","volume":"18","author":"Guan","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12174","DOI":"10.3390\/cimb46110722","article-title":"A Pilot Study of the Total Cholesterol\/High-Density Lipoprotein Ratio as a Prognostic Indicator of Hyperlipidemia-Related Diseases in Dogs and Cats","volume":"46","author":"Choi","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/art.1780360305","article-title":"Chlorambucil. An effective corticosteroid-sparing agent for patients with recalcitrant dermatomyositis","volume":"36","author":"Sinoway","year":"1993","journal-title":"Arthritis Rheum."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0161-6420(01)00864-8","article-title":"Efficacy and safety of chlorambucil in intractable noninfectious uveitis: The Massachusetts Eye and Ear Infirmary experience","volume":"109","author":"Miserocchi","year":"2002","journal-title":"Ophthalmology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1001\/jama.1958.72990200007007c","article-title":"Hepatotoxicity due to chlorambucil: Report of a case","volume":"167","author":"Koler","year":"1958","journal-title":"J. Am. Med. Assoc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1053\/j.seminoncol.2005.11.002","article-title":"Hepatotoxicity of chemotherapy","volume":"33","author":"Floyd","year":"2006","journal-title":"Semin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/0016-5085(86)90183-6","article-title":"Randomized trial of chlorambucil for primary biliary cirrhosis","volume":"91","author":"Hoofnagle","year":"1986","journal-title":"Gastroenterology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.2460\/javma.242.11.1534","article-title":"Metronomic administration of chlorambucil for treatment of dogs with urinary bladder transitional cell carcinoma","volume":"242","author":"Schrempp","year":"2013","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1200\/JCO.1985.3.11.1455","article-title":"Cisplatin combination chemotherapy versus chlorambucil in advanced ovarian carcinoma: Mature results of a randomized trial","volume":"3","author":"Williams","year":"1985","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1001\/jama.1964.03070010029005","article-title":"Chlorambucil-prednisolone therapy for disseminated breast carcinoma","volume":"189","author":"Freckman","year":"1964","journal-title":"JAMA"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Phan, L.M., and Rezaeian, A.-H. (2021). ATM: Main features, signaling pathways, and its diverse roles in DNA damage response, tumor suppression, and cancer development. Genes, 12.","DOI":"10.3390\/genes12060845"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kreis, N.-N., Louwen, F., and Yuan, J. (2019). The multifaceted p21 (Cip1\/Waf1\/CDKN1A) in cell differentiation, migration and cancer therapy. Cancers, 11.","DOI":"10.3390\/cancers11091220"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.dnarep.2016.04.008","article-title":"Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage","volume":"42","author":"Karimian","year":"2016","journal-title":"DNA Repair"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Qian, S., Wei, Z., Yang, W., Huang, J., Yang, Y., and Wang, J. (2022). The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.985363"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/8\/660\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:28:39Z","timestamp":1760034519000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/8\/660"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,15]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["cimb47080660"],"URL":"https:\/\/doi.org\/10.3390\/cimb47080660","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,15]]}}}