Transport anticancer drug

Mata, J. F., et al. Role of the human concentrative nucleoside transporter (hCNTl) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. Mol. Pharmacol. 2001, 59, 1542— 1548. 

Like the glucose carrier, the carriers for large neutral amino acids, the so-called L-system - now designated LAT - are present at both sides of the endothelial cell membranes and transport at least 10 essential amino acids. The L-transporter at the BBB has a much higher transport capacity than those in other tissues. Its marked preference for phenylalanine analogs explains why the anticancer drugs melphalan and d,l-NAM-7 are transported by the L-system, as is the L-Dopa used to treat Parkinson s disease [42]. 

Tsuji A (1998) P-glycoprotein-mediated efflux transport of anticancer drugs at the blood- Van Bree rain barrier. Therap Drug Monitor 20 588-590... 

MDR1 Transport of many xenobiotics out of cells Increased expression confers resistance to certain anticancer drugs inhibition increases blood levels of digoxin... 

As active transport uses a carrier system, it is normally specific for a particular substance or group of substances. Thus, the chemical structure of the compound and possibly even the spatial orientation are important. This type of transport is normally reserved for endogenous molecules such as amino acids, required nutrients, precursors, or analogues. For example, the anticancer drug 5-fluorouracil (Fig. 3.6), an analogue of uracil, is carried by the pyrimidine transport system. The toxic metal lead is actively absorbed from the gut via the calcium transport system. Active uptake of the toxic herbicide paraquat into the lung is a crucial part of its toxicity to that organ (see chap. 7). Polar and nonionized molecules as well as lipophilic molecules may be transported. As active transport may be saturated, it is a zero-order rate process in contrast to passive diffusion (Fig. 3.3). 

This anthracydine type anticancer drug has a quinone moiety so can easily accept an electron and undergo redox cycling. As a result, it interferes with the mitochondrial electron transport chain, damages mitochondrial DNA, and leads to ATP depletion. The result is a dose-dependent cardiomyopathy. 

Nakamoto, Y., Fujiwara, M., Naguchi, T., Kimura, T., Muranishi, S., and Sezaki, H. (1975) Studies on pharmaceutical modi. cation of anticancer drugs. I. Enhancement of lymphatic transport of mitomycin C by parenteral emulsiofthem. Pharm. Bull., 23 2232-2238. 

TFP (5) was the first phenothiazine demonstrated to modulate MDR in drug-resistant P338 murine leukemia cells. TFP (5) enhanced intracellular accumulation of vincristine and adriamycin (77) in resistant tumor cells by inhibiting outward transport of these anticancer drugs [167]. Studies per-... 

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