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The carcinogenic potential of antineoplastic agents can be viewed as a long-term toxic risk, first identified in animal experiments 25 years ago. In 1967, Schmahl was reported on the carcinogenic activity of cyclophosphamide and triazichone in rats. His group, as well as others, extended this field of research during the following years (Schmahl 1986). The findings were later paralleled by the clinical experience that antineoplastic treatment induced second tumors in patients who had been treated for cancer or for other diseases such as autoaggressive diseases, benign hyperprolifer-ations, contracture of Dupuytren, or multiple sclerosis (Kornhuber et al. 1987). Thus, the predictive value of earlier animal experiments was corroborated. Today, as a result of large epidemiologic studies, the carcinogenic risk to humans of antineoplastic agents has been ranked into different categories of carcinogenicity, as shown in Table 1 (Kaldor et al. 1988, 1990a, b; Fraser et al. 1989; Schmahl 1987). Interestingly, these categories very closely reflect the risk classification of anticancer agents obtained from animal studies, which can be summarized as follows: A high risk of inducing second cancer is associated with the use of alkylating agents or cisplatin, the continuous administration of relatively low dosages of antineoplastic agents and regimens inducing high immunosuppression. A low second cancer risk is given with the use of antimetabolites, vinca alkaloids, the intermittent administration of relatively high (“pulse”) doses and regimens inducing low immunosuppression. Having identified the hazard of second cancer induction and largely estimated the current risk to humans, toxicologie research currently mainly concentrate on strategies in limiting this risk. This chapter will focus on some strategies to reduce this risk, as conducted at the Institute of Toxicology and Chemotherapy of the German Cancer Research Center during the last 15 years (Berger 1991). |
