Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice

Abstract

Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule.

Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia

“…Lack of hepatotoxicity in our model may have been due to confounding effects of the weight loss caused by PEG-ASNase, or secondary to the relatively low dose used in our study, compared to other animal studies in which PEG-ASNase induced notable toxicity [20,42]. However, others have found that lower doses of native ASNase decreased serum asparagine to undetectable levels [43,44]. Based on these studies and the limited supply of PEG-ASNase available to us during our study, we administered a single dose of 94 IU/mouse (~2466 IU/kg or ~8,032 IU/m 2 ) of PEG-ASNase.…”

Nanoliposomal L-Asparaginase and Its Antitumor Activities in Lewis Lung Carcinoma Tumor-Induced BALB/c Mice

“…In our study, both free and liposomal L-ASP isolated from P. carotovorum showed strong activity against various solid cancer cell lines, including lung, liver, and breast carcinomas and pluripotent human embryonic carcinoma cells. Shiromizu et al reported similar activity of L-ASP in colon cancer (C-26), a murine sarcoma cell line (S-180), and murine breast cancer (4T1) [13].…”

“…When liposomes are loaded with enzymes, they can be targeted to organs such as the spleen, liver, and bone marrow [11], prolonging the circulation time without inhibiting enzymatic activities [12]. L-ASP was clarified for its antitumor activities in breast tumor bearing mice by Shiromizu et al [13]. However, liposomal L-ASP has been only reported for its improvement in vivo anticancer activities in lymphomatic mice [11].…”

Produção de L-asparaginase por Pichia pastoris em cultivos descontínuos-alimentados em biorreatores.

“…Essas cepas apresentam melhorias como maior produtividade e menor imunogenicidade, sendo mais interessantes para aplicações terapêuticas (BATOOL et al, 2016;BRUMANO et al, 2019). Apesar dos estudos com bactérias serem majoritários e apenas ASNases bacterianas serem aprovadas para aplicação clínica, enzimas produzidas em eucariotos tem alto potencial de aplicação terapêutica devido à similaridade com proteínas humanas e menor probabilidade de reação imunológica (LOPES et al, 2017;SHRIVASTAVA et al, 2012). Em vista dessas vantagens, inúmeras cepas recombinantes de leveduras também têm sido desenvolvidas para expressar a ASNase bacteriana ou fúngica.…”

“…Por exemplo, o uso de L-asparaginase no tratamento de outros linfomas (linfoma nasal, linfoma não Hodgkin, e leucemia mieloide aguda), e inclusive em animais (Saba, Hafeman, Vail, & Thamm, 2009). Ademais, há um grande potencial como antitumoral para o câncer de mama (SHIROMIZU et al, 2018) e como agente inibitório da evolução deste câncer para metástase (KNOTT et al, 2018). Acrescentam-se estudos em outros tumores sólidos, tais como câncer pancreático (DUFOUR et al, 2012) e de ovários (LORENZI et al, 2006).…”