Cancer Chelating agents

Polyamines and their ammonium salts have been of interest because they are known to have potential applications as chelating agents (1-3), ion exchange resins (4-6), flocculants (7,8), and other industrial uses (9). Recent biomedical applications have constituted another important use of polymeric amines they have been investigated for use as biocompatable materials, polymeric drugs, immobilization of enzymes, cell-culture substratum and cancer chemotherapeutic agents (10-12). 

Subramanian, R., and Meares, C.F. (1991) Bifunctional chelating agents for radiometal-labeled monoclonal antibodies. In Cancer Imaging with Radiolabeled Antibodies (D.M. Coldenberg, ed.), pp. 183-199. Kluwer, Boston, MA. 

Applications for the 1,10-phenanthroline nucleus are widespread for example, they have been used as chelating agents (see Section 10.23.5.2), ligands for catalysis (see Section 10.23.5.2), as cytotoxic drugs <2002T9095>, and, when complexed with molybdenum, as cancer therapeutics <2005W0087783>. 

The main dose-limiting toxicity of all anthracyclines is myelosuppression, with neutropenia more commonly observed than thrombocytopenia. In some cases, mucositis is dose-limiting. Two forms of cardiotoxicity are observed. The acute form occurs within the first 2-3 days and presents as arrhythmias or conduction abnormalities, other electrocardiographic changes, pericarditis, and myocarditis. This form is usually transient and is asymptomatic in most cases. The chronic form results in a dose-dependent, dilated cardiomyopathy associated with heart failure. The chronic cardiac toxicity appears to result from increased production of free radicals within the myocardium. This effect is rarely seen at total doxorubicin dosages below 500-550 mg/m2. Use of lower weekly doses or continuous infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin of 300 mg/m2. All anthracyclines can produce "radiation recall reaction," with erythema and desquamation of the skin observed at sites of prior radiation therapy. 

Curnov A,McIlroy BW, Postle-Hacon MJ, Porter JB,MacRobert AJ,Bown SG. Enhancement of 5-aminolaevulinic acid induced photodynamic therapy using hydroxypyridi-none iron chelating agents. Br J Cancer 1998 78 1278. 

Earlier we mentioned that the chelating agent EDTA is used in the treatment of lead poisoning. Certain platinnm-containing compounds can effectively inhibit the growth of cancerous cells. A specific case is discussed on p. 898. 

Doxorubicin Intercalator, forms free radicals, inhibits topoisomerase Hodgkin, breast, endometrial, lung, and ovarian cancers BMS—delayed CHF (dexrazoxane is an iron-chelating agent preventing the formation of free radicals it is not a free radical trapper ), alopecia, vesicant, radiation recall ... 

The cellular levels of iron and ferrochelatase are important determinants of PpIX yield under exogenous ALA stimulation. The use of iron chelators is based on the relative inefficiency of ferrochelatase compared to other enzymes, which causes PpIX build-up when heme precursors are produced at an increased rate. In some cancer cell lines lower levels of ferrochelatase have been found than in normal cells and this may contribute to tumor selectivity in certain cancers [197]. In an attempt to further reduce or totally abrogate heme formation, exogenous chelating agents were used to remove iron. It was shown in vitro that iron chelation caused both increased PpIX formation and improved PDT efficacy and in vivo applications in animals and humans have confirmed the concept [191,198,199]. In lymphocytes that express the transferrin receptor (CD71), which is interpreted as an indication of low intracellular iron levels, higher PpIX concentrations were reached under ALA stimulation [200]. In addition, an analysis of iron availability at the molecular level... 

Watanabe N, Goodwin D A, Meares C F, et al. (1994). Immmunogenicity in rabbits and mice of an antibody-chelate conjugate Comparison of (S) and (R) macrocyclic enantiomers and an acyclic chelating agent. Cancer Res. 54 1049-1054. 

---