Pharmacokinetics and biodistribution of Erufosine in nude mice--implications for combination with radiotherapy - PubMed (original) (raw)

Pharmacokinetics and biodistribution of Erufosine in nude mice--implications for combination with radiotherapy

Guido Henke et al. Radiat Oncol. 2009.

Abstract

Background: Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice.

Methods: NMRI (nu/nu) nude mice were treated by intraperitoneal or subcutaneous injections of 5 to 40 mg/kg body weight Erufosine every 48 h for one to three weeks. Erufosine-concentrations were measured in brain, lungs, liver, small intestine, colon, spleen, kidney, stomach, adipoid tissue, and muscle by tandem-mass spectroscopy. Weight course, blood cell count and clinical chemistry were analyzed to evaluate general toxicity.

Results: Intraperitoneal injections were generally well tolerated in all dose groups but led to a transient loss of the bodyweight (<10%) in a dose dependent manner. Subcutaneous injections of high-dose Erufosine caused local reactions at the injection site. Therefore, this regimen at 40 mg/kg body weight Erufosine was stopped after 14 days. No gross changes were observed in organ weight, clinical chemistry and white blood cell count in treated compared to untreated controls except for a moderate increase in lactate dehydrogenase and aspartate-aminotransferase after intensive treatment. Repeated Erufosine injections resulted in drug-accumulation in different organs with maximum concentrations of about 1000 nmol/g in spleen, kidney and lungs.

Conclusion: Erufosine was well tolerated and organ-concentrations surpassed the cytotoxic drug concentrations in vitro. Our investigations establish the basis for a future efficacy testing of Erufosine in xenograft tumor models in nude mice alone and in combination with chemo- or radiotherapy.

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Figures

Figure 1

Figure 1

Serum concentrations of Erufosine after a single bolus injection (A+B) or repeated injections (C+D). A+B: NMRI nu/nu mice were treated with one intraperitoneal injection of 40 mg/kg body weight Erufosine and subdivided into three groups for blood collection at different time points: group 1, n = 6 (◇): 15 min, 30 min, 1, 2 hours; group 2, n = 5 (□): 30 min, 2, 4, 8 hours; group 3, n = 5 (black triangle): 1, 4, 12, 24 and 36 hours. Erufosine concentrations in serum were determined by LC-MS/MS analysis. Data represent means ± SD: A. Data show the initial serum concentrations of groups 1-3 separately. B. Data show mean Erufosine serum-concentrations for all animals from group 1-3 pooled (n = 16). Insert shows the pharmacokinetic parameters. C+D: NMRI nu/nu mice were treated with repeated intraperitoneal injections of Erufosine every 48 hours at the indicated concentrations. All values are means ± SD (n = 3-6). Erufosine concentrations in serum were determined by LC-MS/MS analysis. C. Concentration-dependent increase in the serum levels of Erufosine after a three weeks treatment with 5, 10, 20 and 40 mg/kg body weight Erufosine. D. Time course of the Erufosine serum concentrations after treatment with 20 and 40 mg/kg body weight Erufosine for one and three weeks.

Figure 2

Figure 2

Biodistribution of Erufosine after repeated drug injections. Mice were separated into 24 groups and treated every 48 hours with a intraperitoneal or subcutaneous injection of Erufosine at the indicated concentrations for one, two or three weeks. At the end of the treatment period mice were killed, organs removed and organ concentrations of Erufosine were determined by LC-MS/MS analysis. All values are means ± SD (n = 3-9). A. Organ concentrations of Erufosine after intraperitoneal treatment with 5, 10, 20 and 40 mg/kg body weight Erufosine for one (left panel), two (middle panel) or three weeks (right panel). B. Organ concentration of Erufosine after subcutaneous treatment with 5, 10, 20 and 40 mg/kg body weight Erufosine for one (left panel), two (middle panel) or three weeks (right panel). Three weeks subcutaneous treatment with 40 mg/kg body weight Erufosine is missing due to local toxicity.

Figure 3

Figure 3

Accumulation of Erufosine in brain tissue after repeated intraperitoneal drug injections. Mice were treated every 48 hours with intraperitoneal injections of Erufosine at the indicated concentrations for one, two or three weeks. At the end of the treatment period mice were killed, organs removed and organ concentrations of Erufosine were determined by LC-MS/MS analysis. A. Brain and serum concentrations of Erufosine after treatment with 20 mg/kg body weight of Erufosine for 7 d and 21 d, respectively. Data show means ± SD (n = 3-6). B. Mean organ concentrations of Erufosine after treatment with 5, 10, 20 or 40 mg/kg body weight for 14 or 21 days were divided by the mean organ concentrations after the respective treatment for 7 days. Data show means ± SEM of the resulting quotients from all 4 dose groups (n = 12-24).

Figure 4

Figure 4

Urine excretion of Erufosine after repeated intraperitoneal drug injections. NMRI nu/nu mice were treated with intraperitoneal injection of 20 mg/kg body weight and 40 mg/kg body weight (n = 6 each) Erufosine every 48 hours for two weeks. The urine was collected over 24-hours on the last three consecutive days of the treatment period in a metabolic cage. Average urine volumes were determined and concentrations of Erufosine in urine were measured by using LC-MS/MS analysis. Data show (A) the urine concentrations and (B) the total amount of Erufosine (means ± SEM).

Figure 5

Figure 5

Change in body weight of animals upon Erufosine treatment. NMRI nu/nu mice were treated with intraperitoneal injections of 5, 10, 20 und 40 mg/kg body weight Erufosine every 48 hours. Body weight was determined every second day. Values represent means ± SEM of the difference from starting weight in the respective dose groups. A. Body weight after intraperitoneal injections. B. Body weight after subcutaneous injections.

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References

    1. Gatenby RA, Gillies RJ. A microenvironmental model of carcinogenesis. Nature reviews. 2008;8:56–61. doi: 10.1038/nrc2255. - DOI - PubMed
    1. Hermann RM, Wolff HA, Jarry H, Thelen P, Gruendker C, Rave-Fraenk M, Schmidberger H, Christiansen H. In vitro studies on the modification of low-dose hyper-radiosensitivity in prostate cancer cells by incubation with genistein and estradiol. Radiation oncology (London, England) 2008;3:19. doi: 10.1186/1748-717X-3-19. - DOI - PMC - PubMed
    1. Itani W, Geara F, Haykal J, Haddadin M, Gali-Muhtasib H. Radiosensitization by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide under oxia and hypoxia in human colon cancer cells. Radiation oncology (London, England) 2007;2:1. doi: 10.1186/1748-717X-2-1. - DOI - PMC - PubMed
    1. Candelaria M, Garcia-Arias A, Cetina L, Duenas-Gonzalez A. Radiosensitizers in cervical cancer. Cisplatin and beyond. Radiation oncology (London, England) 2006;1:15. doi: 10.1186/1748-717X-1-15. - DOI - PMC - PubMed
    1. Lawrence TS, Blackstock AW, McGinn C. The mechanism of action of radiosensitization of conventional chemotherapeutic agents. Seminars in radiation oncology. 2003;13:13–21. doi: 10.1053/srao.2003.50002. - DOI - PubMed

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