Other gallium compounds

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A gallium-doxorubicin-transferrin conjugate was 100 times more inhibitory to a doxorubicin-resistant MCF-7 human breast cancer cell line than doxorubicin alone, and 10 times more inhibitory than an iron-doxorubicin-transferrin conjugate.130 Ga-TF in conjunction with doxorubicin and other chemother-apeutic agents, sometimes with a preliminary dose of deferoxamine, has shown anti-tumor activity and low toxicity following iv administration to breast cancer patients (J. Head, personal communication, 2004).

Gallium chelated to pyridoxal isonicotinoyl hydrazone (PIH; an iron chelator that can enter cells through a non-TFR-mediated mechanism) (Figure 14.3) was found to be growth inhibitory in a human T-lymphoblastic leukemic CCRF-CEM cells resistant to gallium alone, and was more inhibitory than PIH alone.131

A complex of gallium with 2-acetylpyridine 4N-dimethylthiosemicarbazone and chloride (Figure 14.4) showed IC50 values in the low nanomolar range against ovarian (41M), mammary (SK-BR-3) and colon (SW480) carcinoma cells, though the values were similar to those of the ligand alone.132 Further testing is needed to determine whether the gallium helps target the compound to gallium-avid cancer cells.

Gallium protoporphyrin IX (GaPPIX; Figure 14.5) at concentrations of about 1 mg/ml showed in vitro growth-inhibitory activity against many pathogenic

GaCL

Figure 14.4 Structure of bis(2-acetylpyridine lium(III), gallium(III) tetrachloride

GaCL

Figure 14.4 Structure of bis(2-acetylpyridine lium(III), gallium(III) tetrachloride

4N-dimethylthiosemicarbazone)gal-

bacteria, including Gram-positive and -negative species and mycobacteria,133 and against the malarial parasite Plasmodium falciparum.134 Protoporphyrin IX or gallium alone had approximately one-hundredth the anti-bacterial activity of intact GaPPIX against the most sensitive organisms.133 GaPPIX appears to enter bacteria primarily through heme uptake systems; toxicity may occur by incorporation of the molecule into cytochrome/quinol oxidases, which leads to the generation of reactive oxidative species in locally cytotoxic concentra-tions.133 Human primary fibroblasts exposed to 100 mg/ml GaPPIX for 48 h displayed no decrease in viability, and mice given 25-30 mg/kg ip, followed by four daily ip doses of 10-12 mg/kg, showed no acute toxic effects.133

OH

Figure 14.5 Structure of gallium(III) protoporphyrin IX (GaPPIX)

Figure 14.5 Structure of gallium(III) protoporphyrin IX (GaPPIX)

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