Melphalan availability in hypoxia-inducible factor-1α+/+ and factor-1α–/– tumors is independent of tumor vessel density and correlates with melphalan erythrocyte transport

✍ Scribed by Hans Wildiers; Gunter Guetens; Gert de Boeck; Willy Landuyt; Eric Verbeken; Martin Highley; Ernst A. de Bruijn; Allan T. van Oosterom

• Publisher: John Wiley and Sons
• Year: 2002
• Tongue: French
• Weight: 927 KB
• Volume: 99
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.10391

✦ Synopsis

Abstract

Many tumors are impervious to anticancer agents. Resistance due to lack of cytotoxic penetration into the tumor is often overlooked but can play a significant role in undermining therapy. Insufficient and irregular vascularization of tumors is a possible barrier to drug delivery, but there are others, e.g., impaired vessel permeability and poor interstitial transport. We evaluated the importance of tumor vessel density in the availability of melphalan to tumors. A nude mouse tumor model with different vascularization due to a single‐gene deletion of hypoxia‐inducible factor 1α (HIF‐1α^+/+^ and HIF‐1α^–/–^ embryonic stem cell–derived tumors) was used. The availability of melphalan to HIF‐1α^+/+^ (n = 20) and HIF‐1α^–/–^ (n = 23) tumors was not significantly different (p = 0.12). Furthermore, in the various subgroup analyses accentuating the difference in vessel density, no significant correlation between vessel density and melphalan availability was found. In the second part of the study, melphalan, was demonstrated to be transported in blood in mice with a distribution of 24% in erythrocytes vs. 76% in plasma. A strong correlation (r = 0.93, p < 0.000001) between melphalan concentrations in plasma and erythrocytes was found, indicating an equilibrium between these 2 compartments. Plasma and erythrocyte concentrations of melphalan are correlated with the tumor availability of melphalan (r = 0.66 and 0.64, respectively, both p < 0.001). These data suggest that tumor vessel density is not an important predictor of the tumor availability of small cytotoxic drugs such as melphalan and indicate the importance of erythrocytes in the transport of melphalan. © 2002 Wiley‐Liss, Inc.