Cytotoxic and antitumor properties of bleomycin and several of its metal complexes

Abstract

This study examines the concentration-dependent cytotoxicity and antitumor activity of bleomycin (Blm) and Cu-, Zn-, Fe(III)-, and CoBlm using Ehrlich cells in culture and the Ehrlich ascites tumor. The order of activity in culture under several conditions is CuBlm approximately equal to Blm approximately equal to ZnBlm > Fe(III)Blm > CoBlm approximately equal to control. Short exposures of cells to drugs in the presence or absence of serum produced effects on cell proliferation similar to 48-h incubations. With Blm and CuBlm there was no obvious relationship between cytotoxicity and the modest short-term inhibition of DNA synthesis by the drugs. The antitumor experiments produced qualitatively similar results with the order of antitumor potency being CuBlm > Blm > ZnBlm approximately equal to FeBlm > CoBlm approximately equal to control tumor. The host toxicity produced by these drugs as measured by weight loss had the opposite ordering: CoBlm < FeBlm < ZnBlm < Blm < CuBlm. At therapeutically effective concentrations, FeFlm was significantly less toxic relative to ther other active agents.

Radical-induced DNA damage by cytotoxic square-planar copper(II) complexes incorporating o-phthalate and 1,10-phenanthroline or 2,2′-dipyridyl

“…In one such study, Petering et al demonstrated that 50% inhibition of cell growth was obtained upon exposure to $4 mM bleomycin [59], whereas earlier work by the same group showed that just 0.5 mM, over a short incubation time of 60 min, delivered a similar dose-dependent response [58]. Previous work on the lethality of the bleomycin A2 compound toward L5 cells, a derivative of the mouse L cells (B929-L2J), found that 63% inhibition was obtained upon exposure to 12 mg/ml ( $8.5 mM) of the drug, whereas 45 mg/ml ( $32 mM) was required for the similar inhibition of HeLa cells [78].…”

“…The natural chemotherapeutic drug bleomycin (BLM), a powerful metal chelator that also contains a DNA-binding domain, becomes activated in vivo by generating redox-active species upon the binding of first-row transitional metal ions (e.g., Fe 2 þ -BLM or Cu 2 þ -BLM) [57,58]. These DNA-degrading complexes are known to tightly bind to DNA before inducing chemical scission of the 2-deoxyribose ring through the formation of reactive oxygen species (ROS).…”

Copper(II)–Girard's T complex as a promising anti‐tumor agent

“…The addition of copper has been reported to increase the anti‐tumor activity and cytotoxicity of bleomycin (Blm) against Ehrlich ascites tumor in mice for the formed Cu(II)Blm complex 16. Also, some newly synthesized copper(II) complexes of thiosemicarbazones derived from natural aldehydes have a dramatic effect on both cell proliferation and apoptosis in vitro on human leukemia cell line U937 17.…”

Iron requirement for cellular DNA damage and growth inhibition by hydrogen peroxide and bleomycin

“…During the reduction of 02, hydroxyl radicals may be drug. Iron-, copper-and metal-free bleomycin were each active generated, which are highly reactive species and can, for example, against the Ehrlich ascites tumour in mice [26]; Blm remained abstract hydrogen atoms indiscriminately from organic com-active against this tumour in iron-and copper-deficient mice pounds in their vicinity [3][4][5]. Hydroxyl radicals can be produced [16]; metal-restricted incubation conditions did not affect the by the Fenton reaction, in which a reduced transition metal ion cytotoxic activity of Blm or its Fe or Cu complexes in vitro, or complex (Mn+) delivers an electron to H202: though short-term co-incubation of cells with a toxic level of 1,10-phenanthroline did decrease Blm-induced DNA damage H202 + Mn+ *-+ 'OH + OH-+ M(f+')+…”