MEN4901/T-0128, a New Camptothecin Derivative–Carboxymethyldextran Conjugate, Has Potent Antitumor Activities in a Panel of Human Tumor Xenografts in Nude Mice

Abstract

Purpose: The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513. Experimental Design: We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4. Results: MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d × 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d × 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo. Conclusions: Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.

High Antimetastatic Efficacy of MEN4901/T-0128, a Novel Camptothecin Carboxymethyldextran Conjugate

“…In contrast, a single treatment of MEN4901/T-0128 had less effective antitumor activity unless a higher dose was used, indicating repeated treatment regimens were superior to single bolus drug administration. Furthermore, all MEN4901/T-0128 treated animals had tumor regression efficacy against the primary human colon tumor, which was consistent with antitumor activity in human tumor subcutaneous xenografts (9). …”

“…T-0128 has demonstrated a strong antitumor activity against a panel of human tumor subcutaneously implanted in nude mice that were mostly refractory to CPT-11, T-2513, and topotecan (9). These studies could not evaluate antimetastatic efficacy, since they involved subcutaneously-growing tumors which do not metastasize.…”

“…The evaluation of the in vivo antitumor activity of MEN4901/T-0128 against a panel of human tumors implanted subcutaneously in nude mice has demonstrated enhanced antitumor activity and a broad range of therapeutic doses. Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels, which may explain the superior activity of MEN4901/T-0128 in vivo (9). However, these subcutaneous-transplant models generally do not metastasize and could not evaluate the anti-metastatic activity of MEN4901/T0128.…”

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

“…A subsequent study in mice bearing human tumor xenografts found significant tumor inhibition at one third the MTD of 80 mg/kg once a week for four weeks (H81 gastric, 97.5%; H-110 colon, 98.5%; Mqnu-1 lung, 99.7%; H-74 lung, 90.7%; H-204 esophageal, 78.8%; H-181 liver, 81.2%; H48 pancreatic, 98.8%). 292 Pharmacokinetic evaluation of polymer bound SN-38 in nude mice bearing St-4 xenografts found plasma AUC values of 23,900 μg•h/mL and a 30 h half-life after a 40 mg/kg i.v. injection.…”

Polysaccharide-Based Anticancer Prodrugs

“…On the contrary, the treatment with irinotecan and T-2513 was pharmacologically ineffective. The therapeutic treatment with the conjugate did not induce either animal death or weight loss indicating the high therapeutic index with respect to the parent drug [128].…”