The results obtained in this study esablis that liposome formulations incorporating a synthetic polyethylene glycol-derivatied phospholipid have a pronounced effect on liposome tissue dt n and can produce a large increase in the pharmaologial eflkacy of encapsulated antitumor drugs. This effect is i ly greater than that observed previously with conventionl lposomes and is ith a more than 5-fold

No abstract

Although the current clinical formulation of paclitaxel (Taxolt) is an important new anti-cancer agent, it has significant side effects, some of which are related to its formulation in Cremophor/ethanol. Paclitaxel is difficult to formulate for i.v. administration because of its poor aqueous solubility. Here, we report the therapeutic effects of 2 liposome formulations of paclitaxel against human ovarian A121 tumor growing as an s.c. xenograft in athymic nude mice. The liposome formulations used were ETL and TTL, which have 1 or 3 lipid components, respectively. TTL was used as a reconstituted lyophilate or as a stable aqueous suspension. ETL was used as a reconstituted lyophilate only. Both pacli-taxel-liposome formulations were much better tolerated than Taxolt after i.v. or i.p. administration. The acute reactions seen after Taxolt administration did not occur when paclitaxel-liposome formulations were administered. All ETL and TTL preparations significantly delayed A121 tumor growth similarly to Taxol at equivalent doses and schedules. Based on pharmacokinetic data, it is possible that paclitaxel rapidly dissociates from ETL or TTL after i.v. administration and distributes in a manner similarly to Taxol. ETL and TTL formulations may be useful clinically not only for eliminating toxic effects of the Cremophor/ethanol vehicle but also for allowing alterations in route and schedule of drug administration. Int. Paclitaxel is a hydrophobic molecule solubilized for clinical use as an anti-neoplastic agent in Cremophore EL (polyethoxylated castor oil) containing 50% dehydrated ethanol, Taxolt (Bristol Myers Squibb, Princeton, NJ). This formulation has shown significant activity against a broad range of human cancers, including refractory human ovarian and breast cancers, non-small-cell lung carcinoma, head and neck carcinoma and melanoma (Huizing et al., 1995; Rowinsky and Donehower, 1995; Rowinsky et al., 1992). However, Cremophor EL, the excipient used in the Taxol formulation , has been shown to cause serious hypersensitivity reactions in humans (Weiss et al., 1990). To reduce the incidence and intensity of hypersensitivity, pre-medication with corticosteroids (dexametha-sone) and anti-histamines is being used. Although the pre-medication regimen has reduced the incidence of serious hypersen-sitivity reactions to less than 5%, milder reactions still occur in approximately 30% of patients (Weiss et al., 1990; Runowicz et al., 1993). Furthermore, it has been shown that Cremophor EL is mainly responsible for the non-linear pharmacokinetic behavior of paclitaxel in mice, and this may also be the case in humans since the plasma Cremophor concentrations at which non-linearity occurs in mice are in the therapeutic range achieved in humans (Sparreboom et al., 1996). Therefore, there is a strong rationale for reformulating taxanes using a safer and better-tolerated vehicle than Cremophor. Since plain liposomes have little toxicity, formulation of pacli-taxel in liposomes may offer advantages over the cremophor-based form...

DoxilB (Stealth@ liposomal doxorubicin HCI) Injection is doxorubicin HC1incorporated into long circulating liposomes that contain surface-grafted polyoxyethylene chains. These surface-grafted polymer chains reduce the interaction of the liposomes with the mononuclear phagocytic system, accounting for the long circulation and altered biodistribution of Stealth liposomes. They also reduce adhesion of the liposomes to cells, blood vessel walls and other surfaces and result in increased vascular permeability of Stealth liposomes compared to conventional liposomes of equal size. Efficacy studies in several tumor models, including human xenograft models, have demonstrated that Doxil is more effective than unencapsulated doxorubicin (Adriamycin) or doxorubicin encapsulated in non-coated conventional liposomes.. Doxil exhibits altered plasma pharmacokinetics, with a longer plasma half-life, large AUC and markedly smaller volume of distribution than Adriamycin. Tissue levels of doxorubicin are generally lower in Doxil-treated animals than in animals that receive an equivalent dose of Adriamycin, and Doxil is less cardiotoxic, myelotoxic and nephrotoxic than Adriamycin. Phase I and I1 studies evaluating the efficacy of Doxil in AIDS-related Kaposi sarcoma have been encouraging, with evidence of increased delivery of drug to the lesions and an overall good response to therapy. The increased efficacy of Doxil is believed to be related to its increased extravasation through the leaky tumor vasculature and its accumulation in tumor tissue. 1NT;RODUCTIONOptimistic expectations of liposomes as a drug delivery system in the 70's and early 80's were not fulfilled mostly due to their short blood circulation times and quick uptake by mononuclear phagocytic system (MI'S). With the exception of a few applications of drug-loaded liposomes in parasitic diseases of the MI'S, the reduced toxicity of encapsulated therapeutic a gents did not outweigh their reduced efficacy and justify therapeutic applications [l]. 667

THE ability of metal chelates derived from copper and dimethylglyoxime or platinum, palladium and 6-mercaptopurine to inhibit the growth of tumour cells has been demonstrated by Takamiya (1960) and Kirschner, Yung-Kang Wei and Francis (1962) respectively. Further, Lenta and Riehl (1960) have demonstrated the ability of metal chelates derived from ethylene diamine tetraacetic acid (E.D.T.A.) to influence oxidative processes in liver mitochondria isolated from the mouse hepatoma 98/15. Consequently, it seemed likely that other types of metal chelate would have similar actions, especially those derived from the transition metals, Ru, Os, Ni, Fe, Cu, Co, Zn, Cd, and Mn, and substituted 1,10-phenanthroline or related bases, since these substances have been shown to exert marked effects on a wide variety of biological systems including HeLa cells in culture (White, Harris and Shulman, 1963;Shulman and Dwyer, 1964).The present work reports the effect of the following three metal chelates on the growth of the Landschutz ascites tumour in B alb C+ male or C female mice. The marked stability of cations like Ru 2, both to chemical treatment and under biological conditions, suggests that their biological effects are due to the cation as a whole and not to its constituents, the metal and the ligand (Koch, Rogers, Dwyer and Gyarfas, 1957). While it is likely that Cu 1 also acts as the cation, it is possible, since its stability is lower than that of Ru 2, that the constituents of Cu 1 also contribute to its biological action. Further ternary chelates, formed from these constituents and physiological ligands or metals, could likewise contribute to these biological effects (Shulman and Dwyer, 1964). Since stable coordinately-saturated metal chelates are unable to form covalent bonds, their biological actions must be mediated by physical means following their attachment