A novel approach to enhance the activity of
doxorubicin is to increase the availability of cellular "chelatable"
iron to participate in
doxorubicin-mediated
free-radical generation. To achieve this, we designed a regimen consisting of
desferrioxamine (DFO, 50 mg/kg daily given as an i.v. infusion over 72 h) to increase cellular
iron uptake. Thereafter, the combination of
iron sorbitol citrate (ISC) and
doxorubicin (as a single agent or as part of the
CHOP regimen) was given. In a phase I study we investigated the toxicity of this regimen in nine patients with refractory malignant disease. Severe but reversible
ocular toxicity (i.e., acute
maculopathy) was observed in two patients. As these patients were the only ones who were pretreated with
cisplatin, we caution against the use of DFO in
cisplatin-pretreated patients. Severe
phlebitis was encountered in five of nine patients. A partial remission was observed in two of four patients with refractory
Non-Hodgkin's lymphoma who were treated with DFO, ISC, and
doxorubicin as part of the
CHOP regimen. We conclude that pretreatment with DFO and
iron sorbitol citrate may be of benefit in the treatment of
malignancies with
doxorubicin-containing regimens, but
ocular toxicity and severe
phlebitis limits the use of DFO in this approach. The attachment of DFO to biocompatible
polymers may be a method of overcoming the observed toxicity and warrants further study.