Phase I study using desferrioxamine and iron sorbitol citrate in an attempt to modulate the iron status of tumor cells to enhance doxorubicin activity.
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.
Voest
E E
EE
Department of Internal Medicine, University Hospital Utrecht, The Netherlands.
Neijt
J P
JP
Keunen
J E
JE
Dekker
A W
AW
van Asbeck
B S
BS
Nortier
J W
JW
Ros
F E
FE
Marx
J J
JJ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002951:Citrates / Q000008:administration & dosage / Q000009:adverse effects; D019343:Citric Acid; D003676:Deferoxamine / Q000008:administration & dosage / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004338:Drug Combinations; D004357:Drug Synergism; D005123:Eye / Q000187:drug effects; D005260:Female; D005290:Ferric Compounds / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007501:Iron / Q000493:pharmacokinetics*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D013012:Sorbitol / Q000008:administration & dosage / Q000009:adverse effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
D002951:Citrates; D004338:Drug Combinations; D005290:Ferric Compounds; C008170:citric acid, iron, sorbitol drug combination; D019343:Citric Acid; D013012:Sorbitol; D004317:Doxorubicin; D007501:Iron; D003676:Deferoxamine