chapter  3
16 Pages

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 ).