Phase I study of the cytotoxic agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.
N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a new DNA-intercalating drug with a dual mode of cytotoxic action that is thought to involve topoisomerases I and II. On the basis of novelty of action and promising preclinical activity against solid tumours in mice, DACA was selected for clinical trial under the auspices of the Cancer Research Campaign, United Kingdom. We report the phase I findings of a 3-h infusion regimen, repeated 3-weekly, of escalating doses through 18-1000 mg/m2 given to 31 patients with solid malignancies. A maximum tolerated dose (MTD) of 750 mg/m2 was identified, with 3 of 6 cycles being abandoned at 1000 mg/m2. Dose-limiting toxicity took the form of infusional arm pain, in some cases associated with facial discomfort, that was of rapid onset and subsided quickly on the cessation of infusion. The mechanism is unclear but is modulated to some extent by the rate of drug delivery, and it was unaffected in this study by concurrent anti-inflammatory or opiate medication. No host or tumour anti-proliferative activity was observed at these doses, and only minimal toxicity of any other kind was evident. Animal data suggest that the MTD achieved with this schedule may be sub-therapeutic in humans. It is therefore important that efforts be continued to explore methods of giving higher doses of DACA.
McCrystal
M R
MR
Department of Clinical Oncology, Auckland Hospital, New Zealand. meganb@ahsl.co.nz
Evans
B D
BD
Harvey
V J
VJ
Thompson
P I
PI
Porter
D J
DJ
Baguley
B C
BC
D000166:Acridines / Q000008:administration & dosage / Q000009:adverse effects*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005157:Facial Pain / Q000139:chemically induced; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000166:Acridines; D000970:Antineoplastic Agents; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide