Subject: iron/pyridoxal/picolinic acid/cancer

From: Tom Hennessy <[email-masked]>
Date: Tue, 2 Jan 2001 08:41:45 -0700 (MST)

I am hoping you may look at the following articles and give me your
opinion as to whether picolinic acid is related to these chelators?
Tom

Subject: pyridoxal/iron chelate

   Br J Haematol 1979 Nov;43(3):443-9
   
Effective iron chelation following oral administration of an
isoniazid-pyridoxal hydrazone.

    Hoy T, Humphrys J, Jacobs A, Williams A, Ponka P
    
   When isoniazid and pyridoxal are mixed in equimolar quantities a
   hydrazone is formed which is able to complex with iron. The oral
   administration of this compound to rats in single doses of 25--100
   mg/kg leads to an increase in faecal iron excretion up to 8 times the
   normal level. In tissue culture the compound is able to remove iron
   from Chang cells. The results suggest that this compound may be of
   potential value for the oral therapy of iron overload.
   
   PMID: 497121, UI: 80042903
     _________________________________________________________________
Subject: pyridoxal/iron chelate

   Blood 1998 Jun 1;91(11):4368-72
   
Biliary iron excretion in rats following treatment with analogs of pyridoxal
isonicotinoyl hydrazone.

    Blaha K, Cikrt M, Nerudova J, Ponka HF
    
   Centre of Industrial Hygiene and Occupational Diseases, National
   Institute of Public Health, Prague, Czech Republic.
   
   Iron overload is a major life-threatening complication of thalassemia
   major and other iron-loading anemias treated by regular blood
   transfusions. Although the clinical manifestations of iron overload
   may be prevented by desferrioxamine, the only iron-chelating drug in
   routine clinical use, this treatment requires subcutaneous infusion of
   desferrioxamine for 12 hours each day. New orally effective iron
   chelators are urgently needed, and pyridoxal isonicotinoyl hydrazone
   (PIH), which was first recognized as an effective iron chelator in
   vitro and subsequently in vivo, shows promise for the treatment of
   iron overload. More recently, over 40 analogs of PIH were synthesized,
   and some of them proved to be very potent in mobilizing 59Fe in vitro
   from 59Fe-labeled cells. In this study, we show that PIH analogs such
   as pyridoxal benzoyl hydrazone, pyridoxal p-methoxybenzoyl hydrazone
   (PMBH), pyridoxal m-fluorobenzoyl hydrazone (PFBH), and
   pyridoxal-2-thiophenecarboxyl hydrazone, compounds previously shown to
   mobilize iron from cells in vitro, are also effective in vivo. All of
   these chelators significantly enhanced biliary excretion of iron
   (measured by atomic absorption spectrophotometry) following their
   intraperitoneal (IP) and/or oral administration to rats. The most
   effective was PFBH, which increased iron concentration in the bile
   about 150-fold, as compared with basal biliary iron concentration,
   within 1 hour following a single IP dose of 0.2 mmol/kg body weight.
   In contrast, desferrioxamine increased the biliary iron concentration
   only 20-fold to 30-fold under the same conditions. Moreover, while
   control rats excreted approximately 0.8 microg Fe in 2 hours,
   treatment with PFBH, PMBH, and desferrioxamine resulted in cumulative
   excretions of 87, 59, and 22 microg Fe, respectively, in the same
   period of time. Interestingly, PMBH was also quite effective following
   gastric administration, resulting in a 6-hour cumulative value of 34
   mg Fe. These compounds are nontoxic and are inexpensive and easy to
   make. Their further evaluation as candidate drugs for the treatment of
   iron overload is warranted.
   
   PMID: 9596686, UI: 98261465
     _________________________________________________________________
   
Subject: pyridoxal/iron chelate

   Blood 1997 Apr 15;89(8):3025-38
   
The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class
as effective antiproliferative agents II: the mechanism of action of ligands
derived from salicylaldehyde benzoyl hydrazone and 2-hydroxy-1-naphthylaldehyde
benzoyl hydrazone.

    Richardson DR, Milnes K
    
   Lady Davis Institute for Medical Research of the Sir Mortimer B.
   Davis-Jewish General Hospital, Montreal, Quebec, Canada.
   
   We have recently screened 36 analogues of the lipophilic iron (Fe)
   chelator, pyridoxal isonicotinoyl hydrazone (PIH), for their
   antiproliferative effect (Richardson et al, Blood 86:4295, 1995). Of
   these compounds, 1 chelator derived from salicylaldehyde benzoyl
   hydrazone (206) and 4 ligands derived from
   2-hydroxy-1-naphthylaldehyde benzoyl hydrazone (308, 309, 311, and
   315) showed pronounced antiproliferative activity, being far more
   effective than desferrioxamine (DFO). The present study was designed
   to investigate in detail the mechanism of action of these PIH
   analogues in a variety of neoplastic cell lines. This investigation
   showed that the analogues were far more active than DFO at inhibiting
   cellular proliferation and 3H-thymidine, 3H-leucine, and 3H-uridine
   incorporation. Additional experiments showed that, in contrast to DFO,
   the 5 analogues were potent at preventing 59Fe uptake from transferrin
   (Tf) and increasing 59Fe release from cells at concentrations as low
   as 10 micromol/L. Examination of the distribution of 59Fe in
   neoplastic cells using native polyacrylamide gel electrophoresis
   (PAGE)/59Fe-autoradiography showed that most of the 59Fe taken up from
   Tf was incorporated into ferritin, although 3 other previously
   unrecognized components (bands A, B, and C) were also identified. Band
   C comigrated with 59Fe-citrate and was chelated on incubation of
   neuroblastoma cells with DFO, PIH, or the PIH analogues, with this
   compartment being the main intracellular target of these ligands.
   Further work showed that the effects of the chelators at inducing
   characteristics consistent with apoptosis or necrosis were cell
   line-specific, and while DFO increased the percentage of cells in the
   G0/G1 phases in all cell types, the effect of analogue 311 on the cell
   cycle was variable depending on the cell line. This study provides
   further evidence for the potential use of these Fe chelators as
   anticancer agents.
   
   PMID: 9108424, UI: 97262010
     _________________________________________________________________
   
Subject: picolinic/iron/cancer

   J Natl Cancer Inst 1982 Jan;68(1):123-6
   
Antitumor activity of picolinic acid in CBA/J mice.

    Leuthauser SW, Oberley LW, Oberley TD
    
   The growth of a solid tumor induced by im implantation of Ehrlich
   ascites tumor cells in inbred CBA/J mice was retarded by treatment
   with an iron chelator, picolinic acid (PLA). Survival of the mice was
   also significantly increased after PLA treatment. However, the iron
   chelator deferoxamine had no such effects; tumor growth was slightly
   enhanced, and survival was decreased.
   
   PMID: 6948122, UI: 82101866
     _________________________________________________________________