Published in Cancer Detection and Prevention 1993; 17(1).

Iron enhances tumor growth

Hie-Won L Hann, MD

Jefferson Medical College and Thomas Jefferson Univ Hospital, Philadelphia, PA 19107 USA

Iron is required for the growth of all living cells. Ribonucleotide reductase, the enzyme that catalyzes the first step in DNA synthesis, is activated by iron. In order for cells to proceed from the GI phase to the S phase, exogenous or endogenous iron is required. On the other hand, iatrogenic iron overload has been associated with neoplasia: parenteral administration of iron dextran has induced sarcomas at the site of injection. Idiopathic hemochromatosis is associated with a high risk of primary liver cancer. To test the hypothesis that iron enhances tumor growth, we have conducted the following investigations: In the first experiment, 3 groups (Balb/cAnNIcr, C(3)H/HeNIcr, DBA/2Halcr) of 15 mice were fed a low-iron (LFe) diet and 3 groups of 15 mice were fed a normal-iron (NFe) diet. When LFe group became iron deficient, mouse tumor cells were injected s.c.: Balb/c mice received colon cancer cells, C(3)H mice liver cancer cells, and DBA mice breast cancer cells. AU mice developed tumors. However, the tumors grew more slowly, and the mean tumor sizes were always smaller in LFe group (p<0.05 in all 3 comparisons). Next, we studied mice congenitally infected with mammary tumor virus (C3H-MTV+). At weaning, mice were divided into 2 groups of NFe and LFe diet. Those on a LFe diet showed a much slower tumor growth rate. An average tumor growth of the LFe group was 62%/week in contrast to 112%/week for NFe group (p<0.02). Next,- human liver cancer cells (PLC/PRF/5) were grown in a medium with or without iron, and the cell growth was compared. The mass of cancer cells grown in the iron-enriched culture was much larger than the mass of tumor cells grown without iron (14.7 gm vs 9.6 gm of cell mass at the end of 6 weeks culture). Next, 3 types of liver cancer cells (PLC/PRF/5, Hep G2, Hep 3B) were incubated with an iron chelating agent, deferoxamine (DFO). Cell death was proportional to the amount of DFO. Furthermore, this cytotoxicity could be reversed when iron was added simultaneously with DFO. Interestingly, normal human diploid cells (WI 38) were resistant to the cytotoxic effective of DFO. In the final experiment, a human hepatocellular carcinoma cell (HCC) line, PLC/PRF/5 (7x10(6)mouse) were transplanted s.c. into athymic nude mice. When tumors reached 200-300 mm(3) in size, mice with comparable tumor sizes were paired; one was treated with DFO (300 mg/kg BW/day, 5 days/week) i.p. while the other received no DFO. Eight pairs of mice with HCC were observed for 5-18 weeks. Mean tumor growth rates (TGR) (mean ± SE) for the untreated and treated mice were 30.5 ± 3.7 mm(3)/week and 11.9 ± 1.5 mm(3)/week (p< 0.02). In the second set of studies, DFO treatment was begun when the tumor size was smaller (100-20D mm(3)). Four pairs of mice were observed for 4-15 weeks. Mean TGR for the 4 untreated mice were 18. I ± 5.1 mm(3)/week. In 2 mice treated with DFO, tumors regressed completely by the 7th week after the initiation of treatment. The 2 -remaining mice on DFO therapy had much slower growing tumors, with a mean TGR of 1.8 ± 0.5 mm(3)/ week. We conclude that: 1) Iron nutrition of the host affects tumor growth; tumors grow better in an iron-rich environment This should be taken into consideration when treating cancer patients, and senior citizens who have a high risk of developing cancer, 2) Iron chelation with deferoxamine may be a useful tool for cancer treatment.

KEY WORDS: Iron, Iron chelation, cancer prevention, deferoxamine.

Paper presented at the International Symposium on Cofactor Interactions and Cancer Prevention; Nice, France; March 17-19, 1993; in the section on Avoidable Risk Factors.