CONICET | Buscador de Institutos y Recursos Humanos

Concomitant tumor resistance (CR) is the phenomenon by which a tumor-bearing host inhibits the growth of secondary tumor implants and eventually metastases, since they are secondary tumors naturally implanted in a primary tumor-bearing host. Although small-sized immunogenic tumors can induce an immunologically T-dependent CR, the mechanisms underlying the most universal manifestation of CR associated with large-sized immunogenic and non-immunogenic tumors remained elusive for years. Recently, using HPLC and MS and MS/MS spectrometry, we could identify circulating meta (m)-tyrosine and ortho (o)-tyrosine (two tyrosine isomers not present in normal proteins) as the main effectors of CR. Previously, we demonstrated that periodic inoculation of m-tyrosine (its anti-tumor effect is 10 times more robust than o-tyrosine) was able to inhibit the growth of spontaneous metastases generated in mice bearing C7HI or LMM3 subcutaneous (sc) tumors, two mammary carcinomas that do not generate CR but are sensitive to the CR generated by other tumors. In this presentation, in an attempt to evaluate the survival of treated-mice, we simulated a clinical situation: 5 x 105 LMM3 tumor cells were inoculated sc in 25 BALB/c mice. At day 20, all the tumors were surgically excised when their volume was 600 mm3. Six mice that were examined at that day revealed the existence of 8 [3-15] (median [range]) macroscopic lung metastases and numerous micro-metastases before the onset of the treatment. The remaining 19 were divided into two groups that received either saline (controls, n=9) or a daily intra-venous injection of m-tyrosine (67 mg/kg, n=10) for the following 35 days. All the controls died at 41± 6 (mean ± SE) days after surgery exhibiting a huge number of macro- and micro-metastases. In contrast, only 2 treated-mice died [days 56 and 104 after surgery]. The remaining 8 remain still alive 9 months after surgery (p