Interaction of nicotine with anticancer treatment

Investigations on the in vivo interaction of nicotine and antineoplastic agents were prompted by the observation that nicotine lowered the carcinogenicity of the alkylating agent methylnitrosourea (MNU) in rats. Since alkylating agents play an important role as antitumor drugs, nicotine may influence the anticancer activity of anticancer drugs, especially alkylating agents. Two tumor models were selected: (a) autochthonous, MNU-induced mammary carcinoma and (b) transplanted rat leukemia L5222. The antitumor drugs investigated were cyclophosphamide (CPA) and 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea (HECNU). Nicotine was administered continuously by Alzet-osmotic minipumps, at a dose of 2.5 and 5 mg/kg daily. Under these conditions the observed nicotine and cotinine plasma levels approximated levels measured in heavy smokers (nicotine peak level, 47 ng/ml; cotinine peak level, 635 ng/ml). In MNU-induced autochthonous mammary carcinoma, a solid hormone-dependent tumor, the combination of HECNU and nicotine yielded greater tumor inhibition than HECNU alone. The anticancer activity of CPA on transplanted L5222-leukemia, on the other hand, was decreased by continuous infusion of nicotine. The interpretation of both results has to take into account the following possibilities of nicotine action: influence on (a) microcirculation, (b) cell proliferation, (c) membrane transport, (d) metabolism of cytotoxic drugs, and (e) hormonal milieu. The results demonstrate that nicotine is able to influence the outcome of antitumor treatment. The mechanism of interaction needs clarification. Additionally, further combination studies with other classes of cytotoxic drugs are warranted.