The long-term objective of the project is to develop systems where drugs are delivered more selectively to tumors, with concomitant reduction in non-specific toxicity, for use in human metastatic cancer. The objective of the proposed research is to enhance the therapeutic efficacy of liposome-entrapped drugs compared with free drugs against several metastatic animal tumors, in particular liver metastases of mouse tumors. These types of model metastatic tumors more closely resemble the types of metastatic tumor normally relatively resistant to chemotherapy in the clinical situation. More selective delivery of drug to the vicinity of the tumor will be achieved by administering standardized liposome preparations varying with respect to biological half-life (by modification of composition) in order to vary rate of leakage of drug from the liposome and by varying liposome size (by different preparation methods) to determine if smaller sized liposomes are more able to deliver drug to tumor than large liposomes after intravenous injection. By combination of these factors we will be able to control and thereby optimize the rate of drug release in the target organ in order to maximize the therapeutic effects (organ-specific drug delivery). In addition, non-drug containing liposomes (for temporary and non-toxic saturation of non-specific liposome binding sites) will be administered before drug containing liposomes to study their effects on the therapeutic efficacy of drug containing liposomes. The therapeutic and pharmacologic studies will be made in conjunction with acute and chronic toxicity studies to determine therapeutic index and determinations will be made of drug and metabolite levels in target tumor tissue and non-target tissues. Bioassays will be used to directly determine tumor cell numbers in target and non-target organs with and without treatment. The drugs to be used will be clinically useful drugs; adriamycin, cytosine-arabinoside, methotrexate and 5-fluorouracil and derivatives.
| Radel, S; Bankusli, I; Mayhew, E et al. (1988) The effects of verapamil and a tiapamil analogue, DMDP, on adriamycin-induced cytotoxicity in P388 adriamycin-resistant and -sensitive leukemia in vitro and in vivo. Cancer Chemother Pharmacol 21:25-30 |
| Mayhew, E; Ito, M; Lazo, R (1987) Toxicity of non-drug-containing liposomes for cultured human cells. Exp Cell Res 171:195-202 |
| Mayhew, E G; Goldrosen, M H; Vaage, J et al. (1987) Effects of liposome-entrapped doxorubicin on liver metastases of mouse colon carcinomas 26 and 38. J Natl Cancer Inst 78:707-13 |
| Rustum, Y M; Radel, S; Campbell, J et al. (1986) Approaches to overcome in vivo anti-cancer drug resistance. Prog Clin Biol Res 223:187-202 |
| Mayhew, E; Rustum, Y M (1985) The use of liposomes as carriers of therapeutic agents. Prog Clin Biol Res 172B:301-10 |
| Weiss, L; Mayhew, E (1985) An approach to the therapy of metastases from cancer of the upper rectum: a working hypothesis. Cancer Drug Deliv 2:19-33 |
