Amino acid and dipeptide derivatives of daunorubicin. 2. Cellular pharmacology and antitumor activity of L1210 leukemic cells in vitro and in vivo

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Abstract
The accumulation of amino acid and dipeptide derivatives of DNR (daunorubicin) was studied in vitro on mouse leukemia L1210 cells. Only Leu-DNR reached accumulation levels close to DNR, while Val-DNR, Ile-DNR and Leu-Leu-DNR reach intermediate values. Intracellular DNR was found when the L210 cells were incubated in the presence of DNR, Leu-Leu-DNR, Leu-Ala-DNR and Leu-DNR. The cytostatic activity of the derivatives in vitro on L1210 cells cannot be correlated with their uptake or conversion into DNR. At equitoxic doses given i.v. on the i.v. inoculated form of L1210 leukemia, all the derivatives are less active than DNR. When given i.v. on the s.c. inoculated L120 leukemia, Leu-DNR, Ala-Leu-DNR and Leu-Leu-DNR are much more active than DNR with a striking increase in ILS and reduction of tumor progression. The superiority of those compounds could be due to their greater hydrophobicity and to their hydrolysis in situ by enzymes secreted by tumor cells or present on the tumor cells surface.