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.