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Albright, C.F. et al.

Albright, Graciani, Han, Yue, Stein, Lai, Diamond, Dowling, Grimminger, Zhang, Behrens, Musselman, Bruckner, Zhang, Jiang, Hu, Higley, Dimeo, Rafalski, Mandlekar, Car, Yeleswaram, Stern, Copeland, Combs, Seitz, Trainor, Taub, Huang, Oliff,

Matrix metalloproteinase- activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity.

Matrix metalloproteinase (MMP)-activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates were excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as a model system to test these prodrugs because these cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 cells, simple MMP-cleavable peptides were primarily metabolized by neprilysin, a membrane-bound metalloproteinase. MMP-selective metabolism in cultured HT1080 cells was obtained by designing conjugates that were good MMP substrates but poor neprilysin substrates. To determine how conjugates were metabolized in animals, MMP-selective conjugates were given to mice with HT1080 xenografts and the distribution of doxorubicin was determined. These studies showed that MMP-selective conjugates were preferentially metabolized in HT1080 xenografts, relative to heart and plasma, leading to 10-fold increases in the tumor/heart ratio of doxorubicin. The doxorubicin deposited by a MMP-selective prodrug, compound 6, was more effective than doxorubicin at reducing HT1080 xenograft growth. In particular, compound 6 cured 8 of 10 mice with HT1080 xenografts at doses below the maximum tolerated dose, whereas doxorubicin cured 2 of 20 mice at its maximum tolerated dose. Compound 6 was less toxic than doxorubicin at this efficacious dose because mice treated with compound 6 had no detectable changes in body weight or reticulocytes, a marker for marrow toxicity. Hence, MMP-activated doxorubicin prodrugs have a much higher therapeutic index than doxorubicin using HT1080 xenografts as a preclinical model.[1]

References

Matrix metalloproteinase-activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity. Albright, C.F., Graciani, N., Han, W., Yue, E., Stein, R., Lai, Z., Diamond, M., Dowling, R., Grimminger, L., Zhang, S.Y., Behrens, D., Musselman, A., Bruckner, R., Zhang, M., Jiang, X., Hu, D., Higley, A., Dimeo, S., Rafalski, M., Mandlekar, S., Car, B., Yeleswaram, S., Stern, A., Copeland, R.A., Combs, A., Seitz, S.P., Trainor, G.L., Taub, R., Huang, P., Oliff, A. Mol. Cancer Ther. (2005) [Pubmed]

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