HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®). Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity.
(R)-Indoleisopropionic acid (I) [(2R)-(3-indolyl)-propionic acid], a metabolite of a Claviceps strain, is formed from l-tryptophan and the intact methyl group of l-methionine. Indoleacetic acid is not incorporated into indoleisopropionic acid. (2R,S), (3S,R)-3-methyltryptophan (β-methyltryptophan, isomer B) was efficiently incorporated, but no evidence for its formation by the organism could be obtained. A hypothetical scheme for the biosynthesis of indoleisopropionic acid is presented. © 1969.
The reaction of the antitumor antibiotic anthramycin with cellular DNA and the ability of normal human fibroblasts cells and xeroderma pigmentosum (XP) cells to respond to this injury has been evaluated. The binding of [15-3H]anthramycin to cellular DNA in human skin fibroblasts occurred in a linear manner up to 6 h. Treatment with unlabeled antibiotic resulted in unscheduled (repair) DNA synthesis in human skin fibroblasts maintained in hydroxyurea, whereas negligible unscheduled DNA synthesis was observed in cells of an excision-defective strain of XP. Confluent nondividing normal skin fibroblast cells were able to remove 86% of the bound anthramycin within 72 h, however XP cells were only able to remove 49% during the same incubation period. These results are discussed in terms of the types of DNA damage produced by anthramycin in vitro and the likely repair pathways involved in removing lesions produced on DNA by anthramycin.