**1. Introduction**

60 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

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#### **1.1 Epidemiology of nasopharyngeal carcinoma**

The non-viral exposure that is most consistently and strongly associated with risk of nasopharyngeal carcinoma (NPC) is the consumption of salt-preserved fish, a traditional staple food in several NPC-endemic areas [1]. In studies of the Chinese population, the relative risk of NPC associated with weekly consumption of salt-preserved fish generally ranges from 1.4 to 3.2, whereas the risk for daily consumption ranges from 1.8 to 7.5 [2-7]. This indicates that consumption frequency of salt-preserved fish is associated with the risk of NPC. However, elevated NPC risk is also associated with other preserved food items, including meats, eggs, fruits, and vegetables [4-15].

In southern China, intake of salted and other preserved foods is particularly high among boat-dwelling fishermen and their families, this is also the population subgroup at highest risk of developing NPC [16]. Salt-preserved foods are a dietary staple in all NPC-endemic populations [14, 17]. Furthermore, salted fish is a traditional weaning food and is fed early and frequently to infants, especially in the Cantonese population [4, 14] and in families of lower socioeconomic status [3, 18]. Childhood exposure, especially at weaning, appears to be more strongly related to NPC risk than exposure during adulthood [3, 4, 14, 15, 17, 19- 21]. This dietary association may partly explain the international distribution of NPC incidence.

The carcinogenic potential of salt-preserved fish is supported by experiments in rats, which develop malignant nasal and nasopharyngeal carcinoma [22-24]. The process of salt preservation is inefficient, allowing fish and other foods to become partially putrefied [25, 26]. As a result, these foods accumulate significant levels of nitrosamines, which are known carcinogens [25, 27-29]. Consumption of salted fish is a significant source of nitrosamines. Total volatile N-nitrosamines, consisting of N-dimethylnitrosamine, N-diethylnitrosamine, N-nitrosopyrrolidine, and N-nitrosopiperidine, are present in salted fish at concentrations of

Chemical Carcinogenesis and Nasopharyngeal Carcinoma 63

epithelium could be induced to develop carcinoma, and was not insusceptible to these

Toth B et al [39] injected benzo(a)pyrene and dimethylbenzanthrere into AKR mice through the posterior nasal orifice. The induced tumors were mainly located at the hard palate and nasal cavity. Pan et al [72] developed a method for inducing NPC in rats. Long thin polyethylene tubes loaded with benzo(a)pyrene, DMBA, or 3-methylcholanthrene (MC) were inserted into the nasopharyngeal cavities of rats under anesthesia, resulting in squamous carcinoma of the nasopharynx. One animal developed a cancerous ulcer on the mucosa of the nasopharynx. This nasopharynx cancer was a grade III squamous cell carcinoma, which malignant cells grew upwards protruding into the cavity or downwards into the stroma. The incidence rates of the respective groups were as high as those in the

Since Magee [40] first described the toxicity and carcinogenicity of dimethylnitrosamine in rats, the carcinogenicity of nitroso-compounds in different animals has aroused increasing interest and received intensive investigation. A series of reports confirmed that nitrosocompounds could induce a variety of malignant tumors in a great number of different animal species [41-44]. Moreover, nitroso-compounds may result from the interaction of nitrites and secondary amines. These precursors are produced from nitrosamines by bacterial action in the acidic environment of stomach or alkaline intestinal contents [45, 46]. The putative role of nitroso-compounds in the induction of NPC has fascinated many researchers. Ho [47] raised the tentative assumption that the high incidence of NPC in Hong Kong was due to the ingestion of salted fish as main protein source. An appreciable amount of dimethylnitrosamine was reportedly detected in salted fish in the markets of Hong Kong [48]. However, a control survey carried out in Guangzhou demonstrated no such

Generally, the saliva of NPC patients has a higher nitrite content and lower nitrate content than that of normal individuals. In addition, the urinary nitrite content of NPC patients was higher than those of normal controls. These differences were statistically significant in Sihui County [49]. It was suggested that nitrate content of saliva from NPC patients might be reduced by microorganisms in oral cavity; however, the precise mechanism needs to be further investigated. Yi Z et al [50] analyzed nitrate levels in saliva and urine samples collected from 75 NPC patients. The nitrate content in the urine sample of these patients was considerably lower than that of normal subjects, whereas the nitrite content was significantly higher in the urine samples of NPC patients. It was proposed that NPC patients might possess certain reduction mechanisms that could reduce nitrates into nitrites, thus resulting in increased urinary excretion of nitrites and enhanced endogenous synthesis of

There were no reports on experimental nasopharyngeal carcinoma induced by nitroso compounds as carcinogens until 1972. Huang et al [24] reported that out of 22 white rats fed with salted fish, four developed nasal tumors but none developed nasopharyngeal cancer. However, in 1972, Pan et al [72, 73] successfully induced NPC in rats using nitroso-

compounds, thus providing new clues in the investigation of the cause of NPC.

carcinogens.

**2.2 Nitrosamines** 

nitroso-compounds.

group of rats treated with DMBA or DEN.

relationship between NPC and the intake of salted fish [4].

0.028 to 4.54 mg/kg [25] and are converted into carcinogenic N-nitrosocompounds including N,N'-dinitrosopiperazine after food intake [26]. N-nitrosodimethylamine is the predominant volatile nitrosamine in salted fish. In addition, some bacteria can also induce conversion of nitrate to nitrite, which forms important carcinogenic N-nitroso compounds [26]. Experiments in rats have demonstrated the carcinogenicity of nitrosamines and Nnitroso compounds such as diethylnitrosamine (DEN), dimethlbenzanthracene anthracene (DMBA), and Dinitrosopiperazine (DNP) [6, 15, 30].
