Inhibition of tumor growth in vivo by damavaricin C derivatives.

/7-Pentyl ether of damavaricin Fc O-pentyl DvFc) preferentially killed human T-cell lymphotropic virus type I (HTLV-I)-transformed cell lines. The mechanism of action of the drug was investigated using MT~4cells. Cytotoxic action was diminished by the removal of «-pentyl DvFc from the culture or by the addition of sulfhydryl compoundssuch as 2-mercaptoethanol and dithiothreitol.The killing activity of «-pentyl DvFc was also diminished by membrane-acting agents including quinidine and diphenylhydantoin. Influx and subsequent efflux of Ca2+ were observed when either HTLV-Iinfected (MT-4 cells) or uninfected cells were treated with «-pentyl DvFc. An efflux of K+ was observed in HTLV-Iinfected MT-4cells immediately after the exposure of the cells to «-pentyl DvFc. The K+efflux, however, was not observed in the uninfected T cells. «-Pentyl DvFcseems to act primarily on the cell surface of MT-4 cells, leading to the perturbation of membrane function. The restoration of cell growth, however, is critically dependent on the presence of dithiothreitol and 2-mercaptoethanol, implying a role for a free sulfhydryl group in the killing activity. 779Damavaricin Fc is an atropisomeric mixture of two compounds produced by treatment of streptovaricin C with oxygenated concentrated ammonia -methanol. Damavaricin Fc, in which the ansa bridge lies above the aromatic nucleus, has the P helicity as well as streptovaricin C, whereas atropisodamavaricin Fc, in which the ansa bridge lies below the aromatic nucleus, has the Mhelicity (Fig. 1)°. To avoid complicating nomenclature, hereafter we will use damavaricin Fc to refer to this atropisomeric mixture. Streptovaricins belong to the ansa-ring class of antibiotics and in addition to antibiotic activity, they also inhibit retrovirus reverse transcriptase activity in vitro. We have previously reported the biological activities of several derivatives of damavaricin Fc including those which have different alkyl ether linkage at the C-19 position of the naphthoquinone ring of the molecule. Someof these derivatives inhibited proliferation of a mouseretrovirus0.Recently, it has been discovered that several retroviruses can cause severe human diseases2"0.HumanT-cell lymphotropic virus type I (HTLV-I) is the causative agent of adult T-cell leukemia5), one of the most aggressive human leukemias, as well as HTLV-Iassociated myelopathy (HAM)6),

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Inhibition of tumor growth in vivo by damavaricin C derivatives.

Cited by 2 publications

References 4 publications

Growth inhibition of virus transformed cells in vitro and antitumor activity in vivo of geldanamycin and its derivatives.

Growth inhibition of virus transformed cells in vitro and antitumor activity in vivo of geldanamycin and its derivatives.

Selective killing of human T cell lymphotropic virus type I-transformed cell lines by a damavaricin Fc derivative.

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