Activity and distribution of iv and oral 4-demethoxydaunorubicin in murine experimental tumors

Abstract

The antitumor activity of 4-demethoxydaunorubicin ( 4DDM ) compared to its parent compound daunorubicin (DM) was investigated in C57BL/6 mice bearing a T-cell lymphoma, the EL-4, chosen because of its sensitivity to this compound. 4DDM was moderately effective against Lewis lung carcinoma and M5076 ovarian reticulosarcoma tumor systems. Against the EL-4 tumor, after either iv or oral treatment, 4DDM had a good therapeutic effect (survival time in treated mice was almost double that in untreated mice) which was comparable to that of iv doxorubicin. Serum and tissue distribution of 4DDM and its reduced metabolite 4- demethoxydaunorubicinol , given either iv or orally at therapeutic doses to EL-4-bearing mice, was then compared with iv DM using a high-performance liquid chromatography technique with fluorimetric detection. DM seemed to be cleared faster and to a greater extent by metabolism than 4DDM , with half-lives after iv treatment of 23 hrs for 4DDM versus 4.6 hrs for DM. The reduced metabolite in serum amounted to greater than 100% of the concentration of the native compound for DM and less than 20% for 4DDM . By both the iv and oral routes, 4DDM appeared to be concentrated and retained in tissues to a proportionally higher extent than DM, with drug exposure being at least twice as high with correspondingly longer half-lives in almost all tissues investigated, including the tumor. Moreover, this demethoxy analog appeared to be somewhat more selective than DM, since the relative capacity of the tumor tissue to accumulate this compound seemed higher than that of other organs (eg, heart and spleen) reported to be targets of toxicity. Oral administration gave more favorable distribution, resulting in the highest tumor to heart and spleen concentration ratio; this suggests a superiority of this route of administration.