Studies on the mechanism of action of the tumour inhibitory triazenes

A series of imidazole and phenyl dialkyi triazenes were synthesized and investigated for their anti-cancer activity in experimental animals. Active triazenes had a broad spectrum of anti-tumour action and like bischloroethylnitrosourea (BCNU) were active against tumours not sensitive to conventional alkylating agents. It was confirmed that at least one N-methyl group was necessary for anti-cancer activity but there was no correlation between dealkylation by liver microsomes and activity since a diethyl triazene was readily dealkylated but not active. A factor appears to be present in normal cell cytoplasm which can detoxify triazenes but which is absent from tumours sensitive to these agents.     

The ubiquitin-proteasome system (UPS) and the mechanism of action of bortezomib

Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade?) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. There have been almost 200 clinical trials with bortezomib, both as a single agent and in combination with other drugs, for various cancers, as listed in the US National Cancer Institute database. However, bortezomib's mechanism of action remains elusive despite enormous progress in our knowledge of the cell biology of the ubiquitin-proteasome system (UPS) and bortezomib-induced signaling events in cancer cells. This review maps a rapidly growing and open body of research in both areas.     

茯苓多糖抗肿瘤作用与机理的实验研究

观察茯苓多糖（ＰＰＳ）对小鼠肉瘤Ｓ１８０细胞、人白血病Ｋ５６２细胞体外增殖的影响，发现ＰＰＳ对两种细胞的增殖均有强烈抑制作用。为探讨其抗肿瘤机理，对Ｓ１８０细胞膜成分进行了分析，结果显示ＰＰＳ与细胞接触２４ｈ，引起细胞膜唾液酸含量升高，膜磷脂含量降低，膜磷脂脂肪酸组成发生明显改变（Ｃ２０：４和Ｃ１４：０降低），与对照组相比，这些变化均有显著差异（Ｐ＜０．０５或Ｐ＜０．０１）；但膜胆固醇含量、膜流动性（Ｃ／Ｐ比值、Ｕ／Ｓ比值）及膜中性脂脂肪酸组成不受影响。将ＰＰＳ与Ｓ１８０细胞膜在适当条件下一同温育，发现ＰＰＳ干扰膜的肌醇磷脂代谢，明显抑制磷脂酰肌醇转换。提示ＰＰＳ的抗癌机理与膜生化特性改变有关，其中对膜磷脂含量、脂肪酸组成和作为膜磷脂组分之一的肌醇磷脂代谢的影响是重要环节。     

Reactivity and mechanism of the action of triazenes. VI. Triazenes and diazo-compounds as modulators of replicative and repair synthesis of DNA

Communication V in [2].     

Studies of the mode of action of antitumour triazenes and triazines—IV. The metabolism of 1-(4-acetylphenyl)-3,3-dimethyltriazene

The metabolism of 1-(4-acetylphenyl)-3,3-dimethyltriazene has been studied in vivo and in vitro in mice. This dimethyltriazene was extensively metabolised in vivo and HPLC analysis of the plasma revealed the presence of two metabolites, the monomethyltriazene, 1-(4-acetylphenyl)-3-methyltriazene, and the arylamine, 4-aminoacetophenone. The dimethyltriazene was also biotransformed in vitro by a 9000 g fraction of mouse liver homogenate to products which were selectively toxic to TLX5 lymphoma cells. HPLC analysis of the products of in vitro metabolism under these conditions showed the presence of the monomethyltriazene but in an amount insufficient to account for the observed cytotoxicity. The monomethyltriazene was itself rapidly biotransformed by a 9000 g fraction of mouse liver homogenate, and by isolated mouse hepatocytes.     

Clastogenic action of chemotherapy in humans (review)

Examinations of the chromosome damaging (clastogenic) action of chemotherapy not only present valuable insights into the genetic hazards for man resulting from the respective drugs, but also can be used for control of success of certain treatments. In addition, those studies may be helpful in detecting "high-risk" individuals and, in consequence, in protecting them from the detrimental action of therapeutics they are highly sensitive to. Clastogenic activity should not be discussed without considering the close correlation between induction of mutations (e.g. chromosome changes) and malignant transformation, as documented by recent evidence on the meaning of point mutations as well as of chromosomal rearrangements in oncogene activation.