MECHANISMS OF ENHANCEMENT OF THE ANTITUMOR-ACTIVITY OF MELPHALAN BY THE TUMOR-BLOOD-FLOW INHIBITOR 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID

Several studies show that the antitumour activity of melphalan (MEL) a nd other alkylating agents can be enhanced by the selective inhibition of tumour blood flow, although the mechanism(s) underlying these inte ractions are unclear. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a new anticancer agent currently in phase I clinical trial, inhibits blo od flow in murine tumours. DMXAA increased the activity of MEL against the MDAH-MCa-4 mouse mammary tumour maximally when MEL was given abou t 2 h after DMXAA, without compromising the maximal dose of the alkyla ting agent that could be given. The plasma pharmacokinetics of MEL wer e unchanged by DMXAA pretreatment, but the area under the concentratio n-time curve (AUG) for the tumour increased by 33% as a result of decr easing clearance (consistent with falling tumour blood flow). However, inhibition of tumour blood flow also leads to microenvironmental chan ges (e.g. acidosis and hypoxia) that might influence sensitivity to ME L. The sensitivity of KHT cells (freshly isolated from tumours) to MEL in vitro was increased by lowering of either pH or oxygen concentrati on (pO(2)), with an overall dose-modifying factor of 15 being recorded for aerobic cells at pH 7.4 versus hypoxic cells at pH 6.5. The cellu lar uptake of MEL by KHT cells was increased by 74% under hypoxia. Thu s, DMXAA appears to augment the antitumour activity of MEL through two different mechanisms, increased exposure (via decreased tumour cleara nce of MEL) and increased sensitivity resulting from changes to the tu mour microenvironment, both of which result from inhibition of tumour blood flow.