Tumor metabolism

Gordon et al. (48) recently performed a pathway-based pharmacogenomic study on rectal cancer treated with chemoradiation in which they evaluated 21 polymorphisms in 18 genes involved in the critical pathways of cancer progression (drug metabolism, tumor microenvironment, cell cycle control, and DNA repair). They applied the CART analysis and found that a classification tree with four genes (lL-8, lCAM-1, TGF-, and... 

German investigators (Brock et al) worked on the creation of alkylating pro-drugs that have cytostatic activity after specific biotransformation in the tumor tissue. Cyclophosphamide (CTX) has well pronounced antitumor activity with the broadest spectrum. It is metabolized to the cytotoxic phosphoamide mustard. In normal tissues with high enzyme level cyclophosphamide is converted to its inactive metabolites (Fig. 2). These differences in biotransformation can explain the relative selectivity of cyclophosphamide towards... 

Procarbazine is metabolized in the liver and possibly in tumor cells to yield a variety of free radical and alkylating species. 

DOX, as EPI seems to form fewer amounts of ROS and secondary alcohol metabolite, (ii) encapsulation of anthracyclines in uncoated or pegylated liposomes that ensure a good drug delivery to the tumor but not to the heart, (iii) conjugation of anthracyclines with chemical moieties that are selectively recognized by the tumor cells, (iv) coadministration of dexrazoxane, an iron chelator that diminishes the disturbances of iron metabolism and free radical formation in the heart, and (v) administration of anthracyclines by slow infusion rather than 5-10 min bolus (Table 1). Pharmacological interventions with antioxidants have also been considered, but the available clinical studies do not attest to an efficacy of this strategy. 

Antimetabolites compete with and possibly oust naturally occurring metabolites required for normal biochemical reactions and lead either to the synthesis of malfunctioning macromolecules and/or blockade of necessary intermediate or final metabolic products that are vital to cell survival. Both processes interfere with DNA synthesis and therefore antimetabolites can be used in cancer treatment, as they inhibit cell division and the growth of tumors. 

Fluorouracil (5-fluorouracil, 5-FU, Fig. 5) represents an early example of rational drag design in that it originated from the observation that tumor cells, especially from gut, incorporate radiolabeled uracil more efficiently into DNA than normal cells. 5-FU is a fluorinated pyrimidine analog that must be activated metabolically. In the cells 5-FU is converted to 5-fluoro-2>deoxyuridine-monophosphate (FdUMP). This metabolite inhibits thymidilate synthase which catalyses the conversion of uridylate (dUMP) to thymidilate (dTMP) whereby methylenetetrahydrofo-late plays the role of the carbon-donating cofactor. The reduced folate cofactor occupies an allosteric site of... 

Lack of oxygen in blood or tissues. Tissue hypoxia can be caused by injury, inflammation, or tumor growth, due to disruption of blood supply. Tissue hypoxia is normally associated with acidosis, as anaerobic metabolism leads to production of lactic acid. 

Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors a review. Cancer Res 49 6449-6465... 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Furthermore, we found that the two types of tumor promoters induced common biological effects, such as irritation of mouse ear, and stimulation of prostaglandin E2 production and of arachidonic acid metabolism in rat macrophages. These common effects seem to be the most essential biological activities in tumor promotion (6). 

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