The effects of N-methylformamide on artificial and spontaneous metastases from a murine hepatocarcinoma

Abstract

Summary The effects of the differentiation-inducing polar solvent N-methylformamide (NMF) on artificially induced and spontaneous metastases from a murine hepatocarcinoma (HCA-1) in C3Hf/Kam mice were investigated. Exposure of HCA-1 cells in vitro for 6 days to 1.0% or 1.25% NMF resulted in an increase in the number of lung nodules formed in mice when these cells were injected into their tail veins. This in vitro NMF exposure increased cell volume and induced only a slight amount of cytotoxicity. Administration of NMF to mice I day before i.v. tumour cell inoculation resulted in a dose-dependent increase in the number of lung nodules formed, beginning at an NMF dose of 600mgkg-1. NMF caused a similar magnitude of metastasis enhancement in immunosuppressed mice. However, when the maximum dose tested (1,800 mg kg-') was administered as 6 daily fractions of 300 mg kg-each, no increase in artificial metastases was detected. Administration of NMF to mice one day after i.v. tumour cell injection resulted in a dosedependent decrease in the number of lung nodules. In mice bearing 5-6mm HCA-1 leg tumours, treatment with 6 daily fractions of NMF (300mg kg-each) significantly reduced the number of spontaneous pulmonary metastases, yet had very little effect on the growth of the primary tumour. These data suggest that, in a clinically relevant treatment setting, NMF can reduce metastasis formation.

N-methylformamide affects spontaneous metastases of 3LL lines and increases natural killer activity of tumor-bearing mice

“…This finding supports data reported in the literature concerning the antimetastatic effect of NMF administered to experimental and human tumors according to different schedulings [18,22,32]. x 12) on different 3LL lines.…”

“…Finally, considering the conflicting data regarding the antitumor efficacy of N MF [10,24,28,31,32], probably due to differences in pharmacologic conditions achieved in preclinical and clinical studies [25], a better knowledge of the mechanism(s) of action and metabolic pathway of this compound appears mandatory for a rational employment in cancer therapy.…”

N-methylformamide induces changes on adhesive properties and lung-colonizing potential of M14 melanoma cells

“…The effect of NMF on spontaneous metastases has also been demonstrated previously in different model systems, and several mechanisms have been postulated for the antimetastatic effect of the agent (Iwakawa et al, 1987;Tofilon et al, 1987;Iwakawa et al, 1989;Greco et al, 1990;Iwakawa et al, 1994). It has been hypothesized that NMF may induce tumour cells to form a less aggressive differentiated phenotype, resulting in a decrease in metastatic potential (Spremulli and Dexter, 1984).…”

“…Depending on the experimental setting, NMF may exert both enhancing and inhibiting effects on tumour metastases. In particular, the enhancement of metastases is observed when murine tumour cells are treated with NMF before intravenous inoculation Takenaga, 1984), whereas there is a reduction when the agent is given after tumour cell inoculation (Iwakawa et al, 1987;Tofilon et al, 1987;Greco et al, 1990;Iwakawa et al, 1994).…”

Metastasizing lung carcinomas in Hann: Wistar rats

“…There are many animal models used in research on tumor metastases, and in these, secondary tumors are produced either by intravascular injection of tumor cells (so-called artificial metastasis) [1][2][3][4][5][6][7][8][9][10][11][12][13][14] or by implantation of tumor cells into soft tissue [2,[15][16][17][18] or into a defined organ (so-called spontaneous metastasis) [2,19]. However, all these models reflect a certain artificiality.…”