M etabolic A ctivation and D etoxification of C ancer Drugs
It has been recently suggested that cancer cell m etabolism plays a crucial role in m etabolic activation and detoxification of chem otherapeutic drugs, horm ones, horm one antagonists, grow th factors (GFs), cytokines and vitam ins, and conse quently profoundly change their therapeutic activity (1-5). M ost of anticancer drugs are acting by changing the cell m etabolism and also their therapeutic activ ity can be enhanced by alterations in cell m etabolism . Cancer drugs can also undergo transform ation or alterations in their interm ediary m etabolism and these m etabolic adaptations m ay ultim ately induce profound changes in biotransfor m ation of anticancer drugs and that drastically change their therapeutic activity (6 , 7). M etabolic activation and detoxification are tw o different phases of the sam e m etabolic process called m ore adequately "biotransform ation" of cancer drugs, w hich includes all phases of interm ediary drug m etabolism and its m etabolizing pathways. This is a com plex and characteristic phenom enon by w hich m ost of anticancer drugs are transform ed from their inactive form (or "prodru g") into an "active drug" in the presence of several m icrosom ial enzym es. W ithout this m eta bolic activation the anticancer drugs w ill rem ain in the "inactive form " for a long period of time. A sim ilar m etabolic activation is required for m ost of chem ical car cinogens, and som e of steroid horm ones, their agonists, growth factors (GFs), cytokines and vitam ins (Fig. 10, Table 8). Also, m ost of chem ical carcinogens m ust first be m etabolized or enzym atically converted from inactive form or "procar cinogen" by m etabolic activation to an activated carcinogen (electrophilic reac tant, R +) or the ultim ate carcinogen. However, som e procarcinogens can undergo a different m etabolic pathway, and be converted to "proxim ate" carcinogens and then to inactive m etabolites (1, 2 ). This stage of m etabolic activation of both car cinogens and non-carcinogenes is carried out by various enzym es called m ono oxygenases that are present in m ost tissues of m an and anim als and located in the m icrosom es on the endoplasm ic reticulum (ER). These enzym es require N A D PH (the reduced form of nicotinam ide adenine dinucleotide) and m olecular oxygen (0 2+) and they consist of an electron-transporting system together w ith a term inal cytochrom e P-450. By using im m unochem ical m ethods and m ainly rat liver, it has been found that m ono-oxygenases are located in the ER as w ell as in the nuclei, having sim ilar m etabolic activities, but those located in the nuclei require the
presence of cytochrom e P-448, w hile that located in ER require the presence of P-450 (1-3). It is also possible that there are differences betw een enzym es involved in m etabolic activation and those involved in detoxification (3). The m etabolism of cancer drugs and carcinogens in hum ans show s large interindividual varia-
Table 8 Com parative M echanism s o f Action at Cellular and M olecular Level in Carcinogenesis
D NA; gene expression ++ + + + m -RN A ; protein synthesis ++ ++ + + + M etabolic activation ++ - - - M utagenicity ++ +* +* +* Cell division ++ ++ + + Cell proliferation ++ + + + + Cell differentiation ++ + + ++ Antioxidation + + + ++ Apoptosis + + + + Cell receptors - ++ ++ + Irreversible changes ++ - - - Latent (Latency) period ++ + + +
tion, as w ell as species and the ethnic variation due to the occurrence and the genetic polym orphism in carcinogen m etablizing enzym es, nam ely N A D (P)H quinone oxidoreductase polym orphism w ith different carcinogenic risks as w ell as im plications for chem otherapy (4, 8 , 9). A lthough the recent data revealed that the N A D (P)H quinone oxidoreductase (NQ01) polym orphism is com m on, they also indicate significant ethnic differences in allele frequencies; hom ozygous vari ants w ere fourfold (20.3% ) m ore com m on am ong A sians com pared w ith C aucasians (5%) or A frican-A m ericans (also 5%). It has also been suggested that the race and ethnic variation and geographical distribution, m ay influence differ ences in drug distribution elim ination, and drug m etabolism and could explain the success of treatm ent in som e cancers (e.g. breast cancer) by the genetic differ ences (genetic heterogeneity) of diverse patient populations, and the possible effects of inherited variation in the genes encoding bioreductive (activating or deactivating) enzym es. This m ay help developing and evaluating bioreductive drugs, and also in the selection of patients to receive specific anticancer therapy. Since 5-20% of patients (depending upon ethnicity) w ill have a dim inished m eta bolic activation of bioreductive com pounds, and thereby the expression of NQ01 in tum ors w ill increase the efficacy of bioreductive chem otherapeutics (8 ). Hence, there are species differences, geographical and ethnic variations in hum an cancer cell m etabolism and its m etabolizing pathways. A lthough m ost know n chem ical carcinogens act directly on nuclear D N A (nDN A), horm ones, growth factors (GFs) or cytokines and vitam ins act differently on DN A, RN A and protein synthesis (Fig. 10, Table 8) (2, 3, 5 -7 ). However, there are carcinogens that act directly on m itochondrial D N A (m t-DN A). Thus, adm inistration of labeled aflatoxin B 1 (3H A FB1) an hepatic carcinogen it w as found to be located prim arily in m t-D N A of hepatocytes, in concentrations three to four tim es higher than in nD N A (nuclear D N A), and this persistent high level of A FB1 in circular m t-D N A than to duplex nD N A can be due to lack of excision system in the m itochondria (10), and suggests m itochondrial D N A (m t-DN A) is a critical target for carcinogens (2 ,10 ).