A Predictive Model of Human Myelotoxicity Using Five Camptothecin Derivatives and the In vitro Colony-Forming Unit Granulocyte/Macrophage Assay

Abstract

Purpose: Many promising anticancer drugs are limited by myelosuppression. It is difficult to evaluate human myelotoxicity before a Phase I study because of the susceptibility of humans and animals to hematotoxicity. The purpose of this study was to establish a reliable method to predict the human maximum tolerated dose (MTD) of five camptothecin derivatives: SN-38, DX-8951f, topotecan, 9-aminocamptothecin, and camptothecin.Experimental Design: The myelotoxicity of SN-38 and DX-8951f were evaluated on bone marrow from mice, dogs, and humans using a 14-day colony-forming unit, granulocyte-macrophage (CFU-GM) assay to determine the 50%, 75%, and 90% inhibitory concentration values (IC 50 , IC 75 , and IC 90 , respectively).Results: Species differences in myelotoxicity were observed for SN-38 and DX-8951f. Using human and murine IC 90 s for myelotoxicity of these compounds and other camptothecin compounds (topotecan, 9-aminocamptothecin, and camptothecin), in vivo toxicological data, and pharmacokinetic parameters (data referred to in the literature), human MTDs were predicted retrospectively. The mechanismbased prediction model that is proposed uses the in vitro camptothecin assay and in vivo parameters on the basis of free fraction of area under the concentration-curve at the MTD (r 2 ‫؍‬ 0.887) and suggests that the human MTDs were well predicted for the five camptothecin derivatives by this model rather than by other models.Conclusion: The human MTDs of the camptothecin drugs were successfully predicted using the mechanismbased prediction model. The application of this model for in vitro hematotoxicology could play an important role for the development of new anticancer agents.

Bone marrow and tumor cell colony-forming units and human tumor xenograft efficacy of noncamptothecin and camptothecin topoisomerase I inhibitors

“…Although human and canine bone marrow may have similar sensitivity to TopoI inhibitors, we found that murine bone marrow is 4.5-to 27-fold less sensitive to these compounds. The differential sensitivity between murine and human bone marrow progenitor cells to TopoI inhibitors may explain, in part, why curative doses/blood levels of topotecan and irinotecan/SN-38 in mice with human tumor xenografts are not achievable in patients (51,52). The corollary is that compounds with smaller or no differential in bone marrow progenitor sensitivity among species would likely have a better potential for reaching similar blood levels in patients as in mice.…”

Genz-644282, a Novel Non-Camptothecin Topoisomerase I Inhibitor for Cancer Treatment

“…Top1 inhibitors kill rapidly dividing bone marrow progenitor cells and tumor cells, resulting in acute reversible neutropenia and thrombocytopenia 4 to 20 days after administration (18). Bone marrow colony-forming unit-granulocyte macrophage (CFU-GM) assays comparing the sensitivity of bone marrow cells across species are useful in predicting the blood levels of an agent that might be achieved with acceptable toxicity in patients (18)(19)(20)(21). In general, murine bone marrow has a lower sensitivity to Top I inhibitors than does human bone marrow.…”

Targeting G-Quadruplex DNA Structures by EMICORON Has a Strong Antitumor Efficacy against Advanced Models of Human Colon Cancer

“…On the basis of these observations, it has been suggested that compounds with little differential in bone marrow sensitivity across species may have greater potential for reaching similar blood levels in patients as in mice (25). So, on the basis of the CFU-GM assay developed by Pessina and colleagues (46) and validated in several studies (26,47,48), we demonstrated that the mouse bone marrow is only about 5-fold less sensitive than human bone marrow, thus suggesting that EMICORON could reach a similar blood levels in humans as in mice. This is in line Real-time tumor dissemination was monitored by the imaging system.…”