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
F. Kratz et al., 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, J DRUG TAR, 8(5), 2000, pp. 305-318
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.