Distribution of nitroimidazoles and L-phenylalanine mustard in mammary adenocarcinoma 16/C tumors

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Abstract
Using the triphenylmethane dye, lissamine green, as an indicator of blood perfusion, we have demonstrated that L-phenylalanine mustard (L-PAM) is differentially distributed in mice bearing mammary adenocarcinoma 16/C tumors. Following i.p. administration, concentrations of L-PAM in various regions of the tumors vary by as much as 10-fold or more between regions of low and high perfusion. Since the nitroimidazoles, metronidazole and misonidazole, increase the cytotoxicity of certain antitumor agents, these compounds were investigated for their ability to increase the distribution of L-PAM into tumor regions of low perfusion. Administration of metronidazole (400 mg/kg) or misonidazole (800 mg/kg) 1 h prior to L-PAM and lissamine green resulted in elevated plasma levels of L-PAM and increased concentrations of L-PAM in tumor regions of high perfusion. A slight increase in the normally low levels of L-PAM in tumor regions of low perfusion was observed but the increase was not statistically significant. In contrast to the uneven distribution of L-PAM, metronidazole and misonidazole were evenly distributed throughout plasma and tumor regions of both high and low perfusion. Bioassay of tumors following in vivo exposure to metronidazole and L-PAM indicated decreased viability in fragments from tumor regions of high perfusion, but not from tumor regions of low perfusion. These studies demonstrate that the nitroimidazoles increased L-PAM levels in plasma and in tumor regions of both high and low perfusion but did not induce a uniform distribution of L-PAM throughout the tumors. The nitroimidazoles may enhance the effectiveness of L-PAM as an antitumor agent by increasing the concentration of drug that reaches a tumor.