The investigational anti-
cancer drug
5,6-dimethylxanthenone-4-acetic acid (
DMXAA) was developed by the Auckland
Cancer Society Research Centre (ACSRC). It has recently completed Phase I trials in New Zealand and UK under the direction of the
Cancer Research Campaign's Phase I/II Clinical Trials Committee. As a
biological response modifier, pharmacological and toxicological properties of
DMXAA are remarkably different from most conventional chemotherapeutic agents. Induction of
cytokines (particularly tumour
necrosis factor (
TNF-alpha),
serotonin and
nitric oxide (NO)), anti-vascular and anti-angiogenic effects are considered to be major mechanisms of action based on in vitro and animal studies. In
cancer patients of Phase I study,
DMXAA also exhibited various biological effects, including induction of
TNF-alpha,
serotonin and NO, which are consistent with those effects observed in in vitro and animal studies. Preclinical studies indicated that
DMXAA had more potent anti-tumour activity compared to
flavone-8-acetic acid (FAA). In contrast to FAA that did not show anti-tumour activity in
cancer patients,
DMXAA (22 mg/kg by
intravenous infusion over 20 min) resulted in partial response in one patient with metastatic cervical
squamous carcinoma in a Phase I study where 65
cancer patients were enrolled in New Zealand. The maximum tolerated dose (MTD) in mouse, rabbit, rat and human was 30, 99, 330, and 99 mg/kg respectively. The dose-limiting toxicity of
DMXAA in
cancer patients included acute reversible
tremor,
cognitive impairment, visual disturbance, dyspnoea and anxiety. The
plasma protein binding and distribution into blood cells of
DMXAA are dependent on species and drug concentration.
DMXAA is extensively metabolised, mainly by glucuronidation of its
acetic acid side chain and 6-methylhydroxylation, giving rise to
DMXAA acyl
glucuronide (
DMXAA-G), and 6-hydroxymethyl-5-methylxanthenone-4-acetic
acid (6-OH-MXAA), which are excreted into bile and urine.
DMXAA-G has been shown to be chemically reactive, undergoing hydrolysis, intramolecular migration and covalent binding. Studies have indicated that
DMXAA glucuronidation is catalysed by
uridine diphosphate glucuronosyltransferases (UGT1A9 and UGT2B7), and 6-methylhydroxylation by
cytochrome P450 (
CYP1A2). Non-linear plasma pharmacokinetics of
DMXAA has been observed in animals and patients, presumably due to saturation of the elimination process and
plasma protein binding. Species differences in
DMXAA plasma pharmacokinetics have been observed, with the rabbit having the greatest plasma clearance, followed by the human, rat and mouse. In vivo disposition studies in these species did not provide an explanation for the differences in MTD. Co-administration of
DMXAA with other drugs has been shown to result in enhanced anti-tumour activity and alterations in pharmacokinetics, as reported for the combination of
DMXAA with
melphalan,
thalidomide,
cyproheptadine, and the bioreductive agent
tirapazamine, in mouse models. Species-dependent
DMXAA-
thalidomide pharmacokinetic interactions have been observed. Co-administration of
thalidomide significantly increased the plasma area of the plasma concentration-time curve (AUC) of
DMXAA in mice, but had no effect on
DMXAA's pharmacokinetics in the rat. It appears that the pharmacological and toxicological properties of
DMXAA as a new
biological response modifier are unlikely to be predicted based on preclinical studies. Similar to many
biological response modifiers,
DMXAA alone did not show striking anti-tumour activity in patients. However, preclinical studies of
DMXAA-
drug combinations indicate that
DMXAA may have a potential role in
cancer treatment when co-administered with other drugs. Further studies are required to explore the molecular targets of
DMXAA and mechanisms for the interactions with other drugs co-administered during combination treatment, which may allow for the optimisation of
DMXAA-based
chemotherapy.