Transient retinal effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA, ASA404), an antitumor vascular-disrupting agent in phase I clinical trials.
OBJECTIVE
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an anticancer vascular-disrupting agent, has induced transient visual symptoms in some patients. Exploratory investigations were undertaken to characterize the visual disturbances in two consecutive phase I trials.


METHODS
Assessments were made in 21 patients before and immediately after a 20-minute IV infusion of DMXAA, including visual acuity, funduscopy, color discrimination, pattern electroretinography (PERG), pattern visual-evoked potentials (VEP), and full-field electroretinography (ERG). Evaluation of late effects was undertaken subsequently in 12 patients before and after 6 weeks of IV DMXAA at one dose per week.


RESULTS
Frequency and intensity of transient visual disturbance increased with DMXAA dose, occurring in two thirds of patients at 3000 mg x m(-2). Symptoms included blurring, flickering, fragmentation, alteration of colors, and contrast and mild photosensitivity, starting during the infusion and resolving completely, usually within 60 minutes. Visual acuity was unchanged but color discrimination was perturbed. Dose-dependent increases in PERG P50 implicit time by up to 23 ms returned toward baseline values within 90 minutes. Prominent transient changes on ERG included prolonged scotopic rod and 30-Hz flicker implicit times and reduced 30-Hz flicker amplitude. In the second trial, no clinically significant sustained effects were detected, although an increase in bright flash a-wave implicit time (P = 0.022) was seen on whole-group analysis. In vitro studies showed nonspecific phosphodiesterase inhibition by DMXAA.


CONCLUSIONS
DMXAA induced acute, transient disturbance of retinal activity consistent with phosphodiesterase inhibition. No clinically significant cumulative effects were noted and most effects occurred at doses higher than those used in ongoing clinical trials (ClinicalTrials.gov numbers, NCT00856336, NCT00863733, and NCT00003697).
Jameson
Michael B
MB
Regional Cancer Centre, Waikato Hospital, Hamilton, New Zealand; the.
Sharp
Dianne M
DM
Sissingh
Jennifer I
JI
Hogg
Christopher R
CR
Thompson
Paul I
PI
McKeage
Mark J
MJ
Jeffery
Mark
M
Waller
Susan
S
Acton
Gary
G
Green
Colin
C
Baguley
Bruce C
BC
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D003119:Color Perception Tests; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography / Q000187:drug effects; D005074:Evoked Potentials, Visual / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D009369:Neoplasms / Q000188:drug therapy; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D012160:Retina / Q000187:drug effects* / Q000503:physiopathology; D012164:Retinal Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D014786:Vision Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D014792:Visual Acuity / Q000187:drug effects; D044004:Xanthones / Q000008:administration & dosage / Q000009:adverse effects*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010726:Phosphodiesterase Inhibitors; D044004:Xanthones; C066668:vadimezan; D015106:3',5'-Cyclic-GMP Phosphodiesterases