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

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 1alpha (HIF-1alpha(+/+) and HIF-1alpha(-/-) embryonic stem cell-derived tumors) was used. The availability of melphalan to HIF-1alpha(+/+) (n = 20) and HIF-1alpha(-/-) (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.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Wildiers H,Guetens G,de Boeck G,Landuyt W,Verbeken E,Highley M,de Bruijn EA,van Oosterom AT

doi

10.1002/ijc.10391

keywords:

subject

Has Abstract

pub_date

2002-06-01 00:00:00

pages

514-9

issue

eissn

0020-7136

issn

1097-0215

journal_volume

pub_type

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