Antitumor Efficacy

Antitumor effects by a single iv dose of DE-310 were compared with those by a single dose or multiple doses of the parent drug DX-8951f, using the Meth A solid tumor model.

In a short-term assay (Fig. 4), DE-310 shrank the tumor by a single treatment (qdx1) at maximum tolerated dose (MTD) and at 1/4 MTD, occurring with no body weight loss at 1/4 MTD, and inhibited tumor growth even at 1/16 MTD. In contrast, DX-8951f (qdx1) showed only an inhibition of tumor growth even at MTD, and daily 5 treatments (qdx5) of DX-8951f at MTD were required to shrink the tumor, while the treatments of DX-8951f (qdx5) at 1/4 MTD inhibited tumor growth with a body weight loss.

Figure 4. Antitumor effects of DE-310 (a single dose) compared with those of the parent drug DX-8951f (a single dose or daily 5 doses) with Meth A solid tumor model (short-term assay). Dose levels of DE-310 and DX-8951 f are expressed as DX-8951.

In a long-term assay (Fig. 5), tumors in mice treated with DE-310 (qdx1) at MTD and at 1/2 MTD had disappeared from the 15th day after the dose, and all 6 mice were tumor-free even on the 60th day, and also DE-310 (qdx1) at 1/4 MTD and at 1/8 MTD resulted in the complete disappearance of tumor masses in 4 out of 6 mice for each dose on the 60th day.

In addition, DE-310 (qdx1) exhibited potent antitumor effects against human tumor xenografts in mice, and also significantly prolonged survival in the lung metastasis model (3LL) and in the liver metastasis model (M5076).

As shown in Fig. 6, DE-310 induced far less myelotoxicity than DX-8951f at doses giving similar degrees of antitumor effect with inhibition ratios (IR) over 90%.

From the results of toxicological studies with mice and dogs, it was also suggested that DE-310 has no critical toxicity other than DX-8951f alone, which miaht be newly produced by the conjugation.

Figure 5. Tumor growth curves and complete response ratios (CR) after a single dose of DE-310 with Meth A solid tumor model (long-term assay).

t20

Number of nutleated cells in bone marrow

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