In Vivo and In Vitro Efficacy of an Acid-Sensitive Albumin Conjugate of Adriamycin Compared to the Parent Compound in Murine Renal-Cell Carcinoma

Abstract

This investigation is part of a continuing effort to develop effective drug delivery systems for anticancer agents using human serum proteins as drug carriers. The purpose of the present study was to compare the in vitro and in vivo activity of Adriamycin and an acid-sensitive Adriamycin-albumin conjugate (A-HYD2) in murine renal-cell carcinoma (RENCA). The inhibitory efficacy of A-HYD in RENCA cells in vitro was approximately fourfold lower as compared to Adriamycin. In a first in vivo experiment the efficacy of AHYD2 was compared to free Adriamycin at equitoxic doses (doses: 2 x 12 mg/kg for Adriamycin; 4 x 12 mg/kg for A-HYD2, iv over a period of 2 weeks; beginning therapy at day 7 after tumor inoculation: 10 Balb/ c mice per group). Seven of the eight surviving mice in the Adriamycin-treated group manifested clearly visible kidney tumors and ascites at the end of the experiment. In contrast, the 10 mice treated with A-HYD2 showed a complete remission in all cases, with no visible primary tumor. In a second experiment, therapy was started on day 10 to allow for the development of lung metastases, and the efficacy of the compounds was compared at equimolar and equitoxic doses (doses: 2 x 12 mg/kg for Adriamycin; 2 x 12 mg/kg and 4 x 12 mg/kg for A-HYD2, iv over a period of 2 weeks; 6 mice per group). After 24 days mice treated with Adriamycin or A-HYD2 at equimolar doses showed distinct kidney tumors and metastases in the lungs, with the number of metastases being twice as high in the Adriamycin-compared to the conjugatetreated group. Mice treated with A-HYD2 at equitoxic doses, however, showed a complete remission in all cases and no macroscopically visible metastases in the lungs. In summary, the data are a first identication that therapy with acid-sensitive albumin-Adriamycin conjugates could be a promising approach of treating renal-cell cancer.