SYNERGISM BETWEEN N-ACETYLCYSTEINE AND DOXORUBICIN IN THE PREVENTION OF TUMORIGENICITY AND METASTASIS IN MURINE MODELS

The thiol N-acetylcysteine (NAG) is a promising cancer chemopreventive agent which acts through a variety of mechanisms, including its nucle ophilic and antioxidant properties. We have recently shown that NAC in hibits type-IV collagenase activity as well as invasion, tumor take an d metastasis of malignant cells in mice. NAC is also known to attenuat e the cardiotoxicity of the cytostatic drug doxorubicin (DOX, Adriamyc in). The present study was designed to evaluate whether the combinatio n of NAC and DOX treatments in mice injected with cancer cells could a ffect their tumorigenic and metastatic properties. Six separate experi ments were carried out, using a total of 291 adult female mice. In exp erimental metastasis assays, in which BI6-FI0 melanoma cells were inje cted i.v. into (CD-I)BR nude mice, DOX significantly reduced the numbe r of lung metastases when administered i.v. at a dose of 10 mg/kg body weight, 3 days after the i.v. injection of cancer cells. NAC inhibite d lung metastases when added to the medium of cancer cells before thei r i.v. injection. The combined treatment with DOX and NAG, under vario us experimental conditions, was highly effective, showing a synergisti c reduction in the number of mestastases. In tumorigenicity and sponta neous metastasis assays, in which BI6-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice, DOX decreased the number of lu ng metastases when given i.p. at 2 mg/kg body weight. Oral NAC exerted significant protective effects, and considerably prolonged survival o f mice. The combined treatment with DOX and NAC again showed synergist ic effects on the frequency and weight of primary tumors and local rec urrences, and completely prevented the formation of lung metastases in the experiment in which these end-points were evaluated at fixed time s. While injection of DOX 7 days after implantation of cancer cells fa iled to improve the cancer-protective effects of NAG, its injection af ter 1 day resulted in a striking inhibition of lung metastases. These findings demonstrate an evident synergism between DOX (given parentera lly) and NAC (given with drinking water) in preventing tumorigenicity and metastases. The indications of these animal studies warrant furthe r evaluation in clinical trials.