ABSTRACT
Two chromomycin SA analogs, chromomycin SA(3) and chromomycin SA(2), along with deacetylchromomycin A(3) and five previously reported chromomycin analogs were isolated from a marine-derived Streptomyces sp. The structures of the new compounds were determined by spectroscopic methods including 1D and 2D NMR techniques, HRMS and chemical methods. Chromomycin SA(3) and chromomycin SA(2) are the first naturally occuring chromomycin analogs with truncated side-chains. Biological evaluation of chromomycin analogs for cytotoxicity against two non-small cell lung cancer (NSCLC) cell-lines, A549 and HCC44, demonstrated a decrease in cytotoxicity for the truncated sides chain chromomycin analogs.
Subject(s)
Chromomycins/chemistry , Streptomyces/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/toxicity , Chromomycins/isolation & purification , Chromomycins/toxicity , Drug Screening Assays, Antitumor , Magnetic Resonance Spectroscopy , Molecular ConformationABSTRACT
Three structurally related anticancer drugs, mithramycin, chromomycin A3, and olivomycin, exhibited large differences (greater than 100-fold) in their toxicity towards cultured cells from various species. These differences are species related, as all cell lines from any one species showed similar sensitivity to the three drugs. Of the three species examined, namely, human, mouse, and Chinese hamster, human cells were found to be most sensitive to these drugs. However, no significant difference in toxicity was observed between normal human diploid fibroblasts and heteroploid cell lines established from tumors. The above drugs were found to induce mutants at the hypoxanthine-guanine phosphoribosyl-transferase locus (i.e., resistance to 6-thioguanine) and produced DNA strand breaks, in a dose-dependent manner, in cells from all three species. However, the concentrations of these drugs which produced similar mutagenic or DNA strand break responses differed greatly for cells from the three species, and a good correlation was observed between the toxic and the mutagenic concentrations of these drugs for cells from the three species examined. These studies provide strong evidence that the toxic and mutagenic concentrations of different substances could differ greatly between cells from human and other species and indicate that the results of such studies cannot always be extrapolated from animal to human situations. It is suggested that a knowledge of the relative toxicity of any chemical towards cultured cells from human versus test animal should prove of value in extrapolating the results from animal systems to humans.
Subject(s)
Chromomycins/toxicity , Mutagens , Olivomycins/toxicity , Plicamycin/toxicity , Animals , Cell Line , Cricetinae , Cricetulus , DNA , Humans , Mice , Species SpecificityABSTRACT
Three structurally related anticancer drugs, mithramycin, chromomycin A3, and olivomycin, showed large unexpected differences (up to more than 1000 fold) in their toxicity towards cultured cells from various species (human, Chinese hamster, Syrian hamster, and mouse). Among the cell types examined, human cells (both a diploid fibroblast cell strain and HeLa cells) were maximally sensitive to all these drugs, followed by the Syrian hamster kidney cells (BHK 21). The mouse (LMTK- cells) and Chinese hamster (CHO) cells, which were more resistant, showed interesting differences in their sensitivity towards these drugs. For example, whereas the mouse cells were more resistant to mithramycin than CHO cells, the sensitivity pattern was reversed for both chromomycin A3 and olivomycin. In cell extracts derived from human, mouse, and Chinese hamster cells RNA synthesis, which is the cellular target of these drugs, showed identical sensitivity to both mithramycin and chromomycin A3, indicating that the species specific differences in the toxicity to these drugs are at the level of cellular entry of these compounds. Based on the structures of these glycosidic antibiotics and their patterns of toxicity, it is suggested that the intracellular transport of these drugs involves specific interactions between the sugar residues on these compounds and some type of cell surface receptor(s), which differ among different cell types. Some implications of these results for toxicity studies are discussed.
