Antitumor Activity and Pharmacokinetics of a Morpholino‐anthracycline Derivative (KRN8602) against Human Breast Carcinoma Xenografts Serially Transplanted into Nude Mice

The antitumor activity and pharmacokinetics of (7R, 8S, 10S)‐10‐((3‐deamino‐3‐(4‐morpholino)‐2,3,6‐trideoxy‐α‐l‐lyxo‐hexopyranosyl)oxy)‐8‐ethyl‐7,8,9,10‐tetrahydro‐1,6,7,8,11‐pentahydroxy‐5,12‐naphthacenedione hydrochloride (KRN8602) were evaluated using five human breast carcinoma xenografts in nude mice. The maximum non‐toxic dose of KRN8602 was 2 mg/kg by q4d×3 intraperitoneal and peroral administration. KRN8602 showed significant antitumor activity against MX‐1, which is less sensitive to adriamycin, with the chemotherapeutic indices of 13.0 for po administration and 9.5 for ip injection. Although KRN8602 also inhibited the growth of T‐61 significantly, the antitumor activity of this agent against the other three breast carcinoma xenografts was limited. To elucidate this discrepancy, pharmacokinetic analysis and MTT assay were conducted using the KRN8602‐sensitive MX‐1 and KRN8602‐insensitive R‐27. While no differences were observed in the area under the curve and the peak concentration of KRN8602 for each tumor, a difference in the sensitivity of the tumor strains was obvious in MTT assay. The efficacy of this agent seemed to depend on the sensitivity of each type of tumor cell rather than the concentration of agent in tumor tissues. If it were possible to select patients with sensitive tumor cells to this agent by the MTT assay, the phase II trial might be completed within a short period by reducing the number of studied patients.