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5,6-Dimethylxanthenone-4-Acetic Acid (DMXAA): a New Biological Response Modifier for Cancer Therapy

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Abstract

The investigational anti-cancer drug5,6-dimethylxanthenone-4-acetic acid(DMXAA) was developed by the AucklandCancer Society Research Centre (ACSRC). Ithas recently completed Phase I trials inNew Zealand and UK under the direction ofthe Cancer Research Campaign's Phase I/IIClinical Trials Committee. As a biologicalresponse modifier, pharmacological andtoxicological properties of DMXAA areremarkably different from most conventionalchemotherapeutic agents. Induction ofcytokines (particularly tumour necrosisfactor (TNF-α), serotonin and nitricoxide (NO)), anti-vascular andanti-angiogenic effects are considered tobe major mechanisms of action based on invitro and animal studies. In cancerpatients of Phase I study, DMXAA alsoexhibited various biological effects,including induction of TNF-α,serotonin and NO, which are consistent withthose effects observed in in vitroand animal studies. Preclinical studiesindicated that DMXAA had more potentanti-tumour activity compared toflavone-8-acetic acid (FAA). In contrast toFAA that did not show anti-tumour activityin cancer patients, DMXAA (22 mg/kg byintravenous infusion over 20 min) resultedin partial response in one patient withmetastatic cervical squamous carcinoma in aPhase I study where 65 cancer patients wereenrolled in New Zealand. The maximumtolerated dose (MTD) in mouse, rabbit, ratand human was 30, 99, 330, and 99 mg/kgrespectively. The dose-limiting toxicity ofDMXAA in cancer patients included acutereversible tremor, cognitive impairment,visual disturbance, dyspnoea and anxiety.The plasma protein binding and distributioninto blood cells of DMXAA are dependent onspecies and drug concentration. DMXAA isextensively metabolised, mainly byglucuronidation of its acetic acid sidechain and 6-methylhydroxylation, givingrise to DMXAA acyl glucuronide (DMXAA-G),and 6-hydroxymethyl-5-methylxanthenone-4-aceticacid (6-OH-MXAA), which are excreted intobile and urine. DMXAA-G has been shown tobe chemically reactive, undergoinghydrolysis, intramolecular migration andcovalent binding. Studies have indicatedthat DMXAA glucuronidation is catalysed byuridine diphosphateglucuronosyltransferases (UGT1A9 andUGT2B7), and 6-methylhydroxylation bycytochrome P450 (CYP1A2). Non-linear plasmapharmacokinetics of DMXAA has been observedin animals and patients, presumably due tosaturation of the elimination process andplasma protein binding. Species differencesin DMXAA plasma pharmacokinetics have beenobserved, with the rabbit having thegreatest plasma clearance, followed by thehuman, rat and mouse. In vivo disposition studies inthese species didnot provide an explanation for thedifferences in MTD. Co-administration ofDMXAA with other drugs has been shown toresult in enhanced anti-tumour activity andalterations in pharmacokinetics, asreported for the combination of DMXAA withmelphalan, thalidomide, cyproheptadine, andthe bioreductive agent tirapazamine, inmouse models. Species-dependentDMXAA-thalidomide pharmacokineticinteractions have been observed.Co-administration of thalidomidesignificantly increased the plasma area ofthe plasma concentration-time curve (AUC)of DMXAA in mice, but had no effect onDMXAA's pharmacokinetics in the rat. Itappears that the pharmacological andtoxicological properties of DMXAA as a newbiological response modifier are unlikelyto be predicted based on preclinicalstudies. Similar to many biologicalresponse modifiers, DMXAA alone did notshow striking anti-tumour activity inpatients. However, preclinical studies ofDMXAA-drug combinations indicate that DMXAAmay have a potential role in cancertreatment when co-administered with otherdrugs. Further studies are required toexplore the molecular targets of DMXAA andmechanisms for the interactions with otherdrugs co-administered during combinationtreatment, which may allow for theoptimisation of DMXAA-based chemotherapy.

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  1. Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, New Zealand

    Shufeng Zhou & James W. Paxton

  2. Auckland Cancer Society Research Centre, the University of Auckland, Auckland, New Zealand

    Philip Kestell & Bruce C. Baguley

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Zhou, S., Kestell, P., Baguley, B.C. et al. 5,6-Dimethylxanthenone-4-Acetic Acid (DMXAA): a New Biological Response Modifier for Cancer Therapy. Invest New Drugs 20, 281–295 (2002). https://doi.org/10.1023/A:1016215015530

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