tenulin and Carcinoma--Ehrlich-Tumor

Evidence is presented that sesquiterpene lactones or ketones containing the O=CC=CH2 moiety, e.g., tenulin and helenalin, alkylate the thiol group of reduced glutathione and L-cysteine in vitro. A proposal is offered that this mechanism of action is responsible for the observed potent in vivo antitumor activity of these agents in the Ehrlich ascites and Walker 256 carcinosarcoma and to a lesser extent in the P388 leukemic screen. Inhibition of tumor growth is thought to occur due to the O=CC=CH2 system alkylating by rapid Michael addition the SH biological nucleophiles of key regulatory enzymes of nucleic acid and chromatin metabolism. This proposition is in accord with the ability of these agents to inhibit DNA synthesis and gene activity of Ehrlich ascites cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Ascitic Fluid; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Chromatin; Cyclopentanes; Cysteine; DNA, Neoplasm; Glutathione; Histidine; Lactones; Leukemia, Experimental; Leukemia, Lymphoid; Male; Mice; Mice, Inbred DBA; Neoplasm Proteins; Rats; Sesquiterpenes; Sesquiterpenes, Guaiane; Spectrophotometry, Ultraviolet; Time Factors

Helenalin and tenulin injected into CF1 male mice bearing Ehrlich ascites tumors inhibit DNA synthesis and DNA polymerase enzymatic activity in the tumor cells. Helenalin inhibited protein synthesis. Both drugs increased the concentration of adenosine 3',5'-monophosphate, and interfered with glycolytic and mitochondrial energy processes. Cholesterol synthesis was also inhibited, resulting in lower serum cholesterol levels in tumor-bearing animals. Data obtained in vitro indicate that the cyclopentenone-bearing sesquiterpene lactone and related compounds do not alkylate puring bases of nucleic acids but rather undergo a Michael-type addition reaction with the sulfhydryl groups of reduced glutathione and l-cysteine. Thus, the inhibition of cellular enzyme activities and metabolism that has been observed with these drugs might be explained by the occurrence of a Michael-type teaction.

Topics: Alkylation; Animals; Antimetabolites, Antineoplastic; Carcinoma, Ehrlich Tumor; Cholesterol; Cyclic AMP; Cysteine; DNA, Neoplasm; Glycolysis; Lactones; Male; Nucleic Acid Synthesis Inhibitors; Oxygen Consumption; Rats; RNA, Neoplasm; Sesquiterpenes; Sesquiterpenes, Guaiane; Structure-Activity Relationship; Sulfhydryl Compounds