ANTITUMOR-ACTIVITY OF FREE AND LIPOSOME-ENTRAPPED ANNAMYCIN, A LIPOPHILIC ANTHRACYCLINE ANTIBIOTIC WITH NON-CROSS-RESISTANCE PROPERTIES

The lipophilic anthracycline antibiotic annamycin (Ann) was entrapped in liposomes of different size [median diameter: 1.64 mu m, multilamel lar liposomal Ann (L-Ann); 0.030 mu m, small unilamellar Ann (S-Ann)] with >90% entrapment efficiency and tested in vitro against four pairs of sensitive and multidrug-resistant (MDR) tumor cell lines and in vi vo by the i.v. route in five tumor models: advanced s.c. B16 melanoma; s.c. M5076 reticulosarcoma; lung metastases of Lewis lung carcinoma; and s.c. KB and KB-V1 xenografts in nude mice. Predetermined optimal d oses of the different formulations were used and the results were comp ared with doxorubicin (Dox). In vitro, Ann, either in suspension in 10 % dimethyl sulfoxide (F-Ann) (1 mg/ml) or entrapped in liposomes, was able to partially overcome resistance in all four pairs of sensitive a nd MDR KB, 8226, P388, and CEM cell lines (resistance indexes 63, 269, 333, and 356 for Dox versus 4, 5, 19, and 8.7 for L-Ann, respectively ). In vivo, both F-Ann and liposome-entrapped Ann were slightly more e ffective than Dox in inhibiting the growth of advanced s.c. B16 melano ma tumors. L-Ann was markedly more effective than Dox and moderately m ore effective than F-Ann in prolonging the life span of animals bearin g s.c. M5076 and lung metastases of Lewis lung carcinoma tumors. All d rugs were equally effective at optimal doses in delaying the growth of s.c. KB xenografts, whereas all Ann formulations were markedly more e ffective than Dox in delaying the growth of s.c. KB-V1 (MDR) xenograft s. In all in vivo experiments, S-Ann was consistently more effective t han L-Ann and L-Ann was more effective than F-Ann. These results indic ate that (a) Ann is more effective than Dox by the i.v. route against several tumor models and that MDR tumors are partially not cross-resis tant to Ann both in vitro and in vivo, (b) liposomes enhance the in vi vo antitumor properties of Ann, and (c) small liposomes are more effec tive than large liposomes in enhancing Ann antitumor activity.