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  • Title: Comparison of the potency of glycosylated and nonglycosylated recombinant human granulocyte colony-stimulating factors in neutropenic and nonneutropenic CD rats.
    Author: Nohynek GJ, Plard JP, Wells MY, Zerial A, Roquet F.
    Journal: Cancer Chemother Pharmacol; 1997; 39(3):259-66. PubMed ID: 8996530.
    Abstract:
    Recent studies in human bone-marrow culture and healthy human volunteers suggest that lenograstim [glycosylated, recombinant human granulocyte colony-stimulating factor (rHuG-CSF) produced in Chinese hamster ovary (CHO) cells] has greater in vivo potency than filgrastim [nonglycosylated, methionine-extended recombinant human granulocyte colony-stimulating factor (rmetHuG-CSF) produced in Escherichia coli]. To confirm and extend these results we investigated the in vivo potency of both products in normal rats and neutropenic CD rats as an animal model of chemotherapy-induced neutropenia. In normal rats, groups of eight normal male CD rats received four subcutaneous doses of 10, 30, or 100 micrograms/kg filgrastim or lenograstim on days 1-4 of the study, whereas a control group received the vehicle. Blood samples were collected from each animal before treatment (day -5) and on days 2, 3, 5, 8, and 12 of the study for determination of red blood cell (RBC), platelet, white blood cell (WBC), and differential counts. rHuG-CSF and r-metHuG-CSF produced increased WBC counts, principally due to elevated absolute neutrophil counts (ANCs); on days 2, 3, and 5, all groups receiving rG-CSF had ANCs that increased in a progressive and dose-related manner. With the exception of a single value, mean ANCs obtained on days 2, 3, and 5 in lenograstim-treated groups were higher (statistically significant on day 3 at 30 and 100 micrograms/kg and on day 5 at 10, 30, and 100 micrograms/kg) than the respective values obtained in filgrastim-treated groups. No compound-related effect was noted in RBC or platelet parameters. Neutropenia was induced in male CD rats (12 animals/group) with a single intraperitoneal dose of 50 mg/kg cyclophosphamide (CPA) on day 0. On days 1-4, CPA-treated groups were treated with the vehicle (control) or with filgrastim or lenograstim at 30 or 100 micrograms/kg per day. An additional group was not treated with CPA and served as the absolute control group. Blood was collected from alternating subgroups on study day -5 (pretest) and on days 2, 3, 4, 5, 6, 8, 9, and 12 for determination of RBC, platelet, WBC, and differential counts. No major adverse in-life effect was noted in neutropenic rats. Maximal depression of WBCs and ANCs occurred on day 5, followed by recovery to normal values by days 9 (ANC) and 12 (WBC). On day 3 and days 5-9, rHuG-CSF- and metHuG-CSF-treated groups had marked and dose-related increases in WBCs as compared with CPA-treated controls, principally due to elevated ANCs. With the exception of a few values, mean ANC values obtained in lenograstim-treated groups were consistently higher than the respective values obtained in filgrastim-treated groups; the difference was statistically significant on day 3 (30-microgram/kg groups) and on days 6 and 8 (100-microgram/kg groups). In conclusion, treatment of normal and neutropenic CD rats with lenograstim resulted in a dose-related elevation of ANCs that was consistently and significantly higher than the response to identical doses of filgrastim. These results suggest that lenograstim, the glycosylated form of rG-CSF, has superior in vivo potency in normal and neutropenic animals as compared with filgrastim, the nonglycosylated form of rG-CSF.
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