melphalan and helenalin

Levels of glutathione (GSH) in tumour tissue may be important in determining the clinical response to certain anticancer agents. Recent reports have suggested that D,L-buthionine-S,R-sulphoximine (BSO), a specific inhibitor of GSH synthesis, may be used to deplete tumour cell GSH and thus increase the therapeutic ratio of these agents. We have previously shown that 1-naphthol is a potential antitumour agent, and that its possible metabolite 1,4-naphthoquinone is thiol reactive and capable of redox cycling. It was therefore of interest to investigate the effect of pretreatment with BSO, on the toxicity of these agents, to tumour cells. For comparison we included three other cytotoxic agents, melphalan, helenalin and menadione, the toxicities of which are reported to be modulated by intracellular GSH. Depletion of GSH using BSO did not effect the toxicity of 1-naphthol, or 1,4-NQ but did produce slight potentiation of the cytotoxicities of menadione, helanalin and melphalan. The lack of effect of BSO on 1-naphthol and 1,4-NQ is not easily explained but if one also considers the modest potentiation of cytotoxicity+ achieved with the other agents studied, the potential use of BSO in combined chemotherapy is at best rather modest.

Topics: Antimetabolites; Antineoplastic Agents, Phytogenic; Buthionine Sulfoximine; Cell Line; Cell Survival; Colonic Neoplasms; Drug Evaluation, Preclinical; Glutathione; Humans; Melphalan; Methionine Sulfoximine; Naphthols; Naphthoquinones; Sesquiterpenes; Sesquiterpenes, Guaiane; Vitamin K

Topics: Alkylating Agents; Animals; Carcinoma 256, Walker; Cells, Cultured; Chemical Phenomena; Chemistry; Ethylenediamines; Lactams; Leukemia, Experimental; Male; Mice; Rats; Sesquiterpenes; Sesquiterpenes, Guaiane

Several new cyclopentenones related to helenalin have been synthesized as potential alkylating antitumor agents. The procedure involved the transformation of 2-methyl-2-carbethoxycyclopentanone (2) to an ethylene ketal 3, bromination of 3 followed by dehydrobromination to yield a ketal olefin 5, reduction of 5 to the alcohol 6, conversion of 6 to the corresponding hydroxycyclopentenone 7, and estrification of 7 to afford the cyclopentenone esters 8--11. Biological assays indicated that only cyclopentenones possessing a conjugated ester side chain, such as 9 and 10, demonstrated significant in vitro cytotoxicity against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) as well as in vivo antitumor activity in Walker 256 carcinosarcoma in rats and P-388 lymphocytic leukemia in mice.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma 256, Walker; Cells, Cultured; Cyclopentanes; Leukemia, Experimental; Leukemia, Lymphoid; Male; Mice; Mice, Inbred DBA; Rats; Sesquiterpenes; Sesquiterpenes, Guaiane