INVIVO DISTRIBUTION AND ANTITUMOR-ACTIVITY OF LIPOSOMAL 3',5'-O-DIPALMITOYL-5-FLUORO-2'-DEOXYURIDINE

被引：14

作者：

WAALKES, MV

FICHTNER, I

DONTJE, B

LEMM, M

BECKER, M

ARNDT, D

SCHERPHOF, GL

机构：

[1] Laboratory of Physiological Chemistry, University of Groningen, 9712 KZ, Groningen

[2] Zentralinstitut für Krebsforschung, Robert Rössle Institut, 1115, Berlin-Buch

来源：

JOURNAL OF MICROENCAPSULATION | 1992年 / 9卷 / 03期

关键词：

D O I：

10.3109/02652049209021248

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine (FUdR-dipalmitate), a lipophilic prodrug of 5-fluoro-2'-deoxyuridine (FUdR), was incorporated in different types of liposomes. The in vivo distribution and intrahepatic deacylation of liposomal FUdR-dipalmitate was found to be strongly dependent on liposome composition and on drug to lipid ratio, The use of fluid-type liposomes (egg PC/PS/CHOL) rendered FUdR-dipalmitate more susceptible to enzymatic breakdown than solid-type liposomes (DSPC/DPPG/CHOL). A decrease of the retention of the drug in the body was also obtained when FUdR-dipalmitate was incorporated in solid-type liposomes with high drug to lipid ratio (1 : 10) than with low ratio (1:50). In spite of these substantial differences in the rates at which FUdR was liberated from liposomes with different fluidity, size, or drug to lipid ratio, only minor differences in therapeutic effect were observed in a number of murine tumour models (P388 leukaemia, Lewis Lung carcinoma, B16 melanoma and a C26 adenocarcinoma liver metastasis model). The lipophilic prodrug of FUdR exhibited antitumour activity at 100-600 times lower doses than the free drug. However, at these therapeutic doses FUdR-dipalmitate was also far more toxic. This prohibited the use of higher doses to increase antitumour activity.

引用

页码：335 / 346

页数：12

共 28 条

[1]

Van Borssum Waalkes M., Scherphof G.L., Liposome-incorporated 3′,5′-O-dipalmitoyl-5-fluoro-2′-deoxyuridine as a slow-release antitumor drug depot in rat liver macrophages, Selective Cancer Therapeutics, 6, pp. 15-22, (1990)

[2]

Bottcher C.J.F., Van Gent C.M., Pries C., A rapid and sensitive sub-micro phosphorus determination, Analytica Chimica Acta, 24, pp. 203-204, (1961)

[3]

Daemen T., Dontje B.H.J., Veninga A., Scherphof G.L., Oosterhuis J.W., Therapy of murine liver metastases by administration of MDP encapsulated in liposomes, Selective Cancer Therapeutics, 6, pp. 63-71, (1990)

[4]

Ensminger W.D., Rosowski A., Raso V., Levin D.C., Glode M., Come S., Steele G., Frei E., A clinical-pharmacological evaluation of hepatic arterial infusions of 5-fluoro-2′-deoxyuridine and 5-fluorouracil, Cancer Research, 38, pp. 3784-3792, (1978)

[5]

Fichtner I., Arndt D., Stand und Perspektiven der Liposomenforschung, Pharmazie, 44, H11, pp. 752-757, (1989)

[6]

Fichtner I., Arndt D., Reszka R., Antineoplastic activity and toxicity of some alkylating cytostatics (Cyclophosphamide, CCNU, Cytostasan) encapsulated in liposomes in different murine tumour models, Journal of Microencapsulation, 3, 2, pp. 77-87, (1986)

[7]

Fukushima S., Kawaguchi T., Nishida M., Juni K., Yamashita Y., Takahashi M., Nakano M., Selective anticancer effects of 3′-5′-dioctanoyl-5-fluoro-2′-deoxyuridine, a lipophilic prodrug of 5-fluoro-2′-deoxyuridine, dissolved in an oily lymphographic agent on hepatic cancer of rabbits bearing VX-2 tumour, Cancer Research, 47, pp. 1930-1934, (1987)

[8]

Hartmann H.R., Matter A., Antiproliferative action of a novel fluorinated uridine analog, 5′-deoxy-5-fluorouridine, measured in vitro and in vivo on four different murine tumour lines, Cancer Research, 42, pp. 2412-2415, (1982)

[9]

Heidelberger C., Fluorinated pyrimidines, Progress in Nucleic Acids Research and Molecular Biology, 4, pp. 1-50, (1965)

[10]

Heidelberger C., Danenberg P.V., Moran R.G., Fluorinated pyrimidines and their nucleosides, Advances in Enzymology, 54, pp. 57-119, (1983)

← 1 2 3 →