In vitro and in vivo efficacy of acid-sensitive transferrin and albumin doxorubicin conjugates in a human xenograft panel and in the MDA-MB-435 mammacarcinoma model

Acid-sensitive transferrin and albumin conjugates with doxorubicin have rec ently been developed with the aim of circumventing the systemic toxicity an d improving the therapeutic efficacy of this anticancer agent. The in vitro activity of two acid-sensitive transferrin and albumin doxorubicin conjuga tes and free doxorubicin was evaluated in twelve human tumour xenografts us ing a clonogenic assay. The inhibitory effects and the activity profile of the conjugates was, in general, comparable to that of doxorubicin (mean IC7 0-value for doxorubicin = 0.1 muM and 0.1 - 0.4 muM for the conjugates). Su bsequently, the efficacy of an acid-sensitive transferrin and albumin doxor ubicin conjugate, which both incorporated a phenylacetyl hydrazone bond as a predetermined breaking point, was evaluated in the xenograft mamma carcin oma model MDA-MB-435 in comparison to free doxorubicin (dose, i.v.: 2 x 4, 8 and 12 mg/kg). The conjugates showed significantly reduced toxicity (redu ced lethality and body weight loss) with a concomitantly stable or slightly improved antitumour activity compared to free doxorubicin. At the dose of 12 mg/kg mortality was: unacceptably high in the doxorubicin treated group (approximate to 80%); in contrast, no mortality was observed with the conju gate treated animals with body weight loss < 10%. In a further experiment, therapy with the acid-sensitive doxorubicin albumin conjugate at 3 x 12 mg/ kg in the MDA-MB-435 model resulted in a significantly improved antitumour activity over free doxorubicin at its optimal dose of 2 x 8 mg/kg. In concl usion, acid-sensitive transferrin and albumin doxorubicin conjugates can be administered at higher doses than free doxorubicin in nude mice models wit h a concomitant improvement in antitumour activity. Interestingly, there is no pronounced difference between identically constructed transferrin and a lbumin doxorubicin conjugates with regard to in vitro or in vivo efficacy.