Desferrioxamine enhances AIDS-associated Kaposi's sarcoma tumor development in a xenograft model.
Iron is suspected to be involved in the induction and/or progression of various human tumors. More particularly, we have previously shown that iron may be involved in the pathogenesis of Kaposi's sarcoma (KS). We have also shown that the iron chelator desferrioxamine (DFO) has a potent anti-KS activity in vitro, suggesting that it may represent a potential therapeutic approach for the treatment of KS. The present study was designed to investigate the effect of DFO on the growth of human KS xenografts in immunodeficient mice. Unexpectedly, we found that mice treated with DFO (400 mg/kg, 3 times weekly) (n = 30) exhibited a marked enhancement of tumor growth compared with control mice (n = 33) (230 +/- 134 mm(2) versus 143 +/- 70 mm p < 0.01). No enhancement of tumor growth was seen in mice treated with iron-saturated DFO. At least 2 findings suggest that this paradoxic pro-KS activity occurred independently of mice iron stores. First, treatment with DFO had only a marginal effect on ferritin and hematocrit levels. Second, induction of effective iron depletion by an iron-poor diet (6.7 mg iron/kg diet) (n = 23) did not have a deleterious effect on the growth of the KS xenografts. The lesions obtained from the DFO-treated animals exhibited a significantly decreased apoptotic index (p < 0.05), indicating that some antiapoptotic mechanism induced by DFO may be operating in vivo to favour tumor growth. In conclusion, our data show that DFO has a stimulatory effect on KS growth in immunodeficient mice, suggesting that this drug is not indicated in patients with KS.
Department of Renal and Infectious Diseases, Erasme University, Brussels, Belgium. tsimonar@ulb.ac.be
Thierry
T
Simonart
Johan R
JR
Boelaert
Graciela
G
Andrei
Joost J
JJ
van den Oord
Chantale
C
Degraef
Philippe
P
Hermans
Jean-Christophe
JC
Noel
Jean-Paul
JP
Van Vooren
Michel
M
Heenen
Erik
E
De Clercq
Robert
R
Snoeck
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012514:Sarcoma, Kaposi / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D007502:Iron Chelating Agents; D007501:Iron; D001973:Bromodeoxyuridine; D003676:Deferoxamine