Podophyllotoxin and some of its derivatives are cyclolignans currently used for removing warts and in the clinical treatment of malign neoplasms. As such, they have been an objective of the scientific community for decades, in the search for more potent and more selective anticancer agents. Our interest in the chemoinduction of drug selectivity led us to the design and preparation of new podophyllotoxin derivatives by reaction of podophyllic aldehyde with aliphatic, aromatic, and heteroaromatic amines. Several of the resulting imines displayed a significant selectivity against human colon carcinoma cells, even higher than that of the starting aldehyde. Additional biological studies indicate that these derivatives induce microtubule depolymerization, arrest cells at the G2/M phase of cell cycle, and are able to induce a delayed apoptosis after 48 h of treatment, characterized by caspase-3 activation.

A total of 195 subjects, including 141 exposed workers and 54 farmers, were recruited in China to evaluate the usefulness of chromium (Cr) in erythrocytes as a biomarker of exposure to Cr VI . The levels of Cr in red blood cells (RBC) were remarkably elevated even in a group of workers routinely exposed to Cr VI as low as 5-15 μg m −3 and showed a significant exposure-response trend over the exposure range from 0.002 to 1152 μg m −3 (p<0.0001). Multiple linear regression analyses indicated that age and cigarette smoke were not associated with Cr in RBC. However, female subjects had lower Cr in RBC compared with their male counterparts for about the same exposure levels (p<0.05).The genotypes of band III, which encodes for anion transport protein and may regulate across cell membranes, were also identified and included for analysis. The ratios of Cr in RBC to Cr VI exposure were higher in subjects with a wild genotype than in those who had heterozygous or homozygous variant alleles. However, the difference was not statistically significant probably due to the limited number of participating subjects. In addition, 15 of the 141 workers were selected for multiple exposure monitoring and blood sample collections to evaluate the inter-and intraindividual variations of Cr in RBC. Compared with the personal exposure levels, Cr in RBC had small intraindividual variations with a reliability coefficient of 0.88. The study suggests that Cr in RBC may serve as a sensitive and reliable biomarker for long-term exposure to Cr VI .

We have found that ecteinascidin-743 (ET-743) inhibited cell proliferation at 1-10 ng/ml, leading to S and G 2 /M arrest and subsequent apoptosis, and induced early apoptosis without previous cell cycle arrest at 10 -100 ng/ml in cancer cells. ET-743-mediated apoptosis, did not involve Fas/CD95. ET-743 induced c-Jun NH 2 -terminal kinase (JNK) and caspase-3 activation, and JNK and caspase inhibition prevented ET-743-induced apoptosis. ET-743 failed to promote apoptosis in caspase-3-deficient MCF-7 cells, further implicating caspase-3 in its proapoptotic action. Overexpression of bcl-2 by gene transfer abrogated ET-743-induced apoptosis, but cells underwent cell cycle arrest. ET-743 triggered cytochrome c release from mitochondria that was inhibited by Bcl-2 overexpression. Inhibition of transcription or protein synthesis did not prevent ET-743-induced apoptosis, but abrogated ET-743-induced cell cycle arrest. Microarray analyses revealed changes in the expression of a small number of cell cycle-related genes (p21, GADD45A, cyclin G2, MCM5, and histones) that suggested their putative involvement in ET-743-induced cell cycle arrest. These data indicate that ET-743 is a very potent anticancer drug showing dose-dependent cytostatic and proapoptotic effects through activation of two different signaling pathways, namely a transcriptiondependent pathway leading to cell cycle arrest and a transcription-independent route leading to rapid apoptosis that involves mitochondria, JNK, and caspase-3. Ecteinascidin-743 (ET-743)1 is a marine-derived compound isolated from the marine tunicate Ecteinascidia turbinata (1, 2), with a potent cytotoxic activity against a variety of tumors in vitro and in vivo (3-5). The preclinical in vivo experiments with ET-743 showed cytotoxic activity of the drug when administered at g/m 2 dosages, yielding nanomolar plasma concentrations (6, 7). Current phase II clinical trials in Europe and the United States indicate that ET-743 represents a highly promising antitumor agent. However, the mechanism by which ET-743 exerts its anticancer activity remains to be elucidated. ET-743 has been reported to bind to the minor groove of DNA (8, 9), bending DNA toward the major groove (10). DNA-bound ET-743 appeared to modify the interaction between DNA and several transcription factors (11,12). Also, at high concentrations ET-743 and the related synthetic drug phthalascidin, have been reported to target topoisomerase I (13, 14). However, the relevance of these actions for the antitumor activity of ET-743 can be questioned as they are evidenced at drug concentrations much higher than those required for achieving its antitumor effect. On the other hand, ET-743-treated cells have been reported to accumulate in S and G 2 /M phases (15-18).To elucidate the mechanism underlying the anticancer effect of ET-743, we investigated the putative role of apoptosis in ET-743 action as an explanation for its cytotoxic effect. In this work we have found evidence for the induction of c-Jun NH 2 -terminal kinase (JNK)-, mitoch...