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 mamma carcinoma model.
Acid-sensitive transferrin and albumin conjugates with doxorubicin have recently been developed with the aim of circumventing the systemic toxicity and improving the therapeutic efficacy of this anticancer agent. The in vitro activity of two acid-sensitive transferrin and albumin doxorubicin conjugates and free doxorubicin was evaluated in twelve human tumour xenografts using a clonogenic assay. The inhibitory effects and the activity profile of the conjugates was, in general, comparable to that of doxorubicin (mean IC(70) -value for doxorubicin approximately 0.1 microM and 0.1 - 0.4 microM for the conjugates). Subsequently, the efficacy of an acid-sensitive transferrin and albumin doxorubicin conjugate, which both incorporated a phenylacetyl hydrazone bond as a predetermined breaking point, was evaluated in the xenograft mamma carcinoma 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 (reduced 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 ( approximately 80%); in contrast, no mortality was observed with the conjugate 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 conclusion, acid-sensitive transferrin and albumin doxorubicin conjugates can be administered at higher doses than free doxorubicin in nude mice models with a concomitant improvement in antitumour activity. Interestingly, there is no pronounced difference between identically constructed transferrin and albumin doxorubicin conjugates with regard to in vitro or in vivo efficacy.
Kratz
F
F
Tumor Biology Center, Department of Medical Oncology, Clinical Research, 79106 Freiburg, Germany. felix@tumorbio.uni-freiburg.de
Roth
T
T
Fichiner
I
I
Schumacher
P
P
Fiebig
H H
HH
Unger
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D012710:Serum Albumin, Bovine / Q000627:therapeutic use*; D014168:Transferrin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay / Q000379:methods; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D014168:Transferrin; C069982:doxorubicin-BSA conjugate; D012710:Serum Albumin, Bovine; D004317:Doxorubicin