Methods to reduce the toxicity, especially cardiotoxicity, concomitant with enhancement of therapeutic effects, would greatly enhance the clinical usefulness of the anthracycline antibiotic, adriamycin (AM). In several animal systems acute and chronic toxicity can be reduced and anti-tumor activity maintained or enhanced after entrapment of AM in liposomes. The overall goal of the project is to determine the mechanisms of these effects. Studies will be undertaken to determine whether entrapment of AM in welldefined, standardized liposomes alters one or more of the following parameters: (a) direct cellular effects of the agent, (b) in vivo pharmacology and (c) host defense mechanisms, in favor of therapeutic compared to toxic effects. In vitro studies will be undertaken to compare the kinetics and mechanisms of cellular influx and efflux of free and liposome-entrapped AM at different concentrations and for different time periods. Results from these studies will be compared with the intracellular effects of the two dosage forms on DNA, RNA and protein synthesis and membrane functions under the same conditions. Tumor and normal cell lines and living cells isolated from mice will be used in these studies. In vivo studies will be undertaken in mice to determine the pharmacokinetics, organ disposition (including tumor), metabolism and elimination of free and entrapped AM after i.v. bolus injection and i.v. infusion. Studies will be made to evaluate the relationship between the pharmacologic effects and acute and chronic toxicity. The in vivo uptake and effects of free or liposome AM on some tumor and normal cell types will be determined. The major mouse tumor systems to be investigated will be L1210 leukemia, M5076 reticulum cell sarcoma and colon carcinoma 26. For example, using colon tumor 26, studies will be made on cells isolated from subcutaneous tumors, liver """"""""metastases"""""""" (formed after intrasplenic injection of tumor cells), Kuppfer cells and liver parenchyma cells. Studies will also be made to determine the comparative effects of liposomal and free AM on mechanisms of host defense against tumors including possible augmentation of cell mediated cytotoxicity and tumoricidal effects of macrophages. Knowledge gained from these studies should be useful for optimization of therapeutic applications in experimental systems and for possible future preclinical toxicology and clinical studies.
| Mace, K; Mayhew, E; Mihich, E et al. (1988) Alterations in murine host defense functions by adriamycin or liposome-encapsulated adriamycin. Cancer Res 48:130-6 |
| Radel, S; Mayhew, E; Rustum, Y M (1987) Effects of DMDP, a tiapamil analogue, on adriamycin efflux in adriamycin-resistant and -sensitive P388 cells. Anticancer Res 7:1105-8 |
| Weiss, L; Mayhew, E; Ward, P (1986) Drug delivery to tumors. A problem requiring microscopic resolution. Anal Quant Cytol Histol 8:96-101 |
