Human bladder cancer, schistosomiasis,N-nitroso compounds and their precursors

We write in response to the letter of Badawi (2000). Most of the letters to the editor published in this journal are short communications on cancer research, and only exceptionally do they contain observations on previously published articles. One exception is the letter by Badawi (2000), who comments on our report (Abdel Mohsen et al., 1999), erroneously cited simply as "Mohsen" throughout. Badawi's interpretation of our results is biased by several flaws. In his opinion, (i) the detection of N-nitrosodibutylamine (NDBA), a known animal bladder carcinogen, in the urine of study subjects was our chief observation and (ii) we did not consider the other volatile nitrosamines identified as playing a role in human bladder-cancer induction. Our results showed that N-nitrosodimethylamine (NDMA) accounted for about 50% of all nitrosamines, and in the Discussion section of our report, we stated: "In this study its [NDBA] concentration in urine was about one-tenth that of NDMA, so it is likely that the carcinogenic effect of NDMA overwhelmed that of NDBA since NDBA is a less efficient alkylating agent than NDMA". The frequency distribution of detectable NDBA in the study groups was not statistically different (χ2 p = 0.162). The second point Badawi raised is the discrepancy between the urinary nitrate and nitrite levels observed in our study and previously reported data. Compared with urinary nitrate measured in several different populations (Tricker, 1997), the levels we found in control subjects were in the lower tertile and about one-fourth those reported for a different Egyptian population (Tricker et al., 1989). One possible reason is that we used a different method for measuring nitrite and nitrate. Nevertheless, in our cancer patients, both nitrate and nitrite urinary levels were of the same order of magnitude as reported for paraplegic patients (Tricker et al., 1991). The amount of urinary nitrate largely depends on dietary intake and possibly on other lifestyle and environmental factors, which might have changed over the 10-year interval between our study and that of Tricker et al. (1989) and caused the decrease in urinary nitrate levels. We believe that different groups of subjects must be compared within each study rather than between different studies, to avoid bias. In this context, we observed an increase in nitrate urinary excretion in patients with Schistosoma haematobium infection and no tumor, which was not seen in previous studies (Tricker et al., 1989). We have no explanation for this. We suggested that "the 3-fold higher urinary nitrate in S. haematobium patients compared to controls might be due to the synthesis of nitric oxide by stimulated inflammatory cells as well as by urothelial cells. This would also explain the presence of some nitrite in the urine of these patients, this being otherwise difficult to explain since most urine samples were free of bacteria" (Abdel Mohsen et al., 1999). Although Badawi admits this is acceptable in the active phase of the disease, he objects to any possible involvement of inflammatory and urothelial cell nitric oxide synthase in the production of nitrite in S. haematobium–associated bladder cancer because he states: "By the time SABC (S. haematobium–associated bladder cancer) is developed, schistosomiasis is usually inactive and the proportion of inflamed cells is minimal" (Badawi, 2000). He does not consider that tumors themselves induce the recruitment of macrophages (Thomsen and Miles, 1998), and he ignores our sentence "Urinary nitrate was similar to control values in S. haematobium–associated bladder cancer subjects, but nitrite was greatly increased, possibly due to the action of nitrate-reducing bacteria" (Abdel Mohsen et al., 1999). As shown in our report, the sum of urinary nitrate and nitrite did not differ significantly in S. haematobium–infected patients and in cancer patients with or without associated schistosomiasis. At variance with previous studies (Hicks et al., 1977), we reported that most patients with S. haematobium infection but no cancer did not have superimposed urinary bacteria and argued as follows: "This is possibly because the general population is now more conscious of this health problem and people seek medical care early after the onset of the disease, when bacterial infection has not yet developed" (Abdel Mohsen et al., 1999). Again, Badawi ignores this possible explanation and maintains that urinary schistosomiasis is always associated with bacterial infection; this might have been true in the past, but Badawi appears not to consider that human behavior toward this disease might have changed over time, leading to the present results. In the second part of his letter, Badawi tries to discredit our report by stating that we were not aware of studies aimed at understanding the mechanism underlying the development of schistosoma-associated bladder cancer. Anyone who reads our report will easily detect Badawi's partiality in citing phrases out of context so that readers are driven to misinterpretation. Moreover, he claims that we were wrong in saying that urinary N-nitroso compounds and their precursors in bladder-cancer patients with no history of schistosomal infection were not analyzed in previous studies because Kakizoe et al. (1979) had done this. The study by Kakizoe et al. (1979), which is included in the review by Matanoski and Elliot (1981) cited by us, reports results on Canadian subjects. Our point was that Egyptian bladder-cancer patients with no history of schistosomal infection together with Egyptian controls, Egyptian S. haematobium–infected patients and Egyptian schistosoma-associated bladder-cancer patients had not been studied before. Finally, to our knowledge, N-nitroso compounds have not been definitely proved to be human carcinogens and their role in the initiation and progression of bladder tumor can be defined only by work on experimental animals. In conclusion we find Badawi's vehemence unjustified and disrespectful toward the reviewers of our report. We believe that our data, besides confirming previous results, contribute to the understanding of the mechanism underlying the development of bladder cancer associated with schistosomiasis: the absence of bacteria and the presence of nitrite in the urine of S. haematobium–infected patients fit well with the hypothesis of nitric oxide being synthesized by stimulated urothelial cells and macrophages recruited in response to inflammation. Whether nitric oxide is a precursor of N-nitroso compounds or plays a role in bladder cancer causation remains an open question. The presence of urinary N-nitroso compounds and their precursor in bladder-cancer subjects, associated or not with schistosomiasis, supports the idea that these compounds may have a role in both the initiation and progression of the carcinogenic process. Yours sincerely, Mohamed A. Abdel Mohsen, Ashraf A.M. Hassan, Shehata M. El-Sewedy, Tousson Aboul-Azm, Cinzia Magagnotti, Roberto Fanelli, Luisa Airoldi

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