The elevated methionine (MET) requirement for the growth of tumors, first observed by Sugimura in 1959, termed MET dependence, is a potentially highly effective therapeutic target. Proof of this principle is that when MET restriction (MR) was initially established in co-cultures of cancer and normal cells, MET dependence could be exploited to selectively kill cancer cells without killing co-cultured normal cells. MET-dependent cells become reversibly blocked in the late S/G2 phase of the cell cycle under MR enabling selective and effective S-phase chemotherapy against these blocked cancer cells. Subsequent MET repletion with an anti-mitotic drug was totally effective at selectively eliminating the MET-dependent cancer cells enabling the normal MET-dependent cells to take over the culture. We have also observed that the MET analog ethionine (ETH) is synergistic with MR in arresting the growth of the Yoshida sarcoma both in vitro and eliminating metastasis when transplanted to nude mice. MR increased the efficacy of cisplatinum (CDDP) against the MX-1 human breast carcinoma cell line when grown in nude mice. MR increased 5-fluorouracil (5-FU) efficacy on a human gastric cancer xenograft, SC-1-NU, in nude mice. MET-restricted total parenteral nutrition (MR TPN) was effective in Yoshida sarcoma-bearing rats. MR TPN with doxorubicin (DOX) and vincristine (VCR) resulted in significant tumor suppression and prolonged survival of Yoshida-sarcoma-bearing rats. These results were the basis of subsequent studies that used methioninase to effect MR for effective cancer therapy.
Keywords: Cancer; Cell cycle; Cell cycle arrest; Chemotherapy; Diet; Methionine dependence; Methionine restriction; S/G2 phase; Total parenteral nutrition (TPN).