Antitumor effects of two bisdioxopiperazines against two experimental lung cancer models in vivo

Da-Yong Lu,Jian Ding,Bin Xu

doi:10.1186/1471-2210-4-32

Abstract

BackgroundProbimane (Pro), an anti-cancer agent originating in China, was derived from razoxane (ICRF-159, Raz), a drug created in Britain, specifically targeting at cancer metastasis and as a cardioprotectant of anthrocyclines. Pro and Raz are bisdioxopiperazine compounds. In this work, we evaluated the anti-tumor and anti-metastatic effects of Pro and Raz in vivo against two lung tumor models, one of murine origin (Lewis lung carcinoma, LLC) and one of human origin (LAX-83).ResultsAfter determining the lethal dosage of Pro and Raz, we assessed and compared the inhibitory effects of Pro and Raz against primary tumor growth and metastatic occurrences of LLC at the dosage of LD5. Pro and Raz were active against primary tumor growth and significantly inhibited pulmonary metastasis of LLC at same dose-ranges (inhibitory rates > 90 %). Both Raz and Pro were effective in 1, 5, and 9 day administration schedules. Three different schedules of Raz and Pro were effective against the primary tumor growth of LLC (35–50 %). The synergistic anticancer effect of Raz with bleomycin (Ble) (from 41.3 % to 73.3 %) was more obvious than those with daunorubicin (Dau) (from 33.1 % to 56.3 %) in the LLC tumor model. Pro was also seen to have synergistic anti-cancer effects with Ble in the LLC model. Both Raz and Pro inhibited the growth of LAX 83 in a statistically significant manner.ConclusionsThese data suggest that both Raz and Pro may have anti-tumor potentiality and Raz and Pro have combinative effects with Ble or Dau. The potential targets of bisdioxopiperazines may include lung cancers, especially on tumor metastasis. The anti-cancer effects of Raz and Pro can be increased with the help of other anticancer drugs.

Highlights

Probimane (Pro), an anti-cancer agent originating in China, was derived from razoxane (ICRF-159, Raz), a drug created in Britain, targeting at cancer metastasis and as a cardioprotectant of anthrocyclines
Like Raz, Pro exhibits anti-tumor activity both in vivo and in vitro against experimental tumor models in a small scale investigation [6,7] and limited clinical data showed that Pro could inhibit human malignant lymphoma even for those resistant to other anticancer drugs [8]
Antitumor and antimetastatic effects of Pro and Raz on Lewis lung carcinoma (LLC) Antitumor and antimetastatic effects of Pro and Raz on LLC are tabulated in Table 2 and Table 3

Summary

Introduction

Probimane (Pro), an anti-cancer agent originating in China, was derived from razoxane (ICRF-159, Raz), a drug created in Britain, targeting at cancer metastasis and as a cardioprotectant of anthrocyclines. BMC Pharmacology 2004, 4:32 http://www.biomedcentral.com/1471-2210/4/32 responsible for cytotoxic or modulative actions on tumors, an anticancer agent, probimane [1,2-bis (N4-morpholine-3, 5-dioxopeprazine-1-yl) propane; AT-2153, Pro] was synthesized by introducing two morpholine groups into Raz in China.[5]. Like Raz, Pro exhibits anti-tumor activity both in vivo and in vitro against experimental tumor models in a small scale investigation [6,7] and limited clinical data showed that Pro could inhibit human malignant lymphoma even for those resistant to other anticancer drugs [8]. Pro was shown to inhibit lipoperoxidation (LPO) of erythrocytes [12], influence tumor sialic acid synthesis [13] and inhibit the binding of fibrinogen to leukemia cells [14]

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