1. Thiol depletion and chemosensitization on nimustine hydrochloride by methionine-depleting total parenteral nutrition
N Goseki, M Endo Tohoku J Exp Med. 1990 Jul;161(3):227-39. doi: 10.1620/tjem.161.227.
As an adjunct to cancer chemotherapy, we had succeeded in creating the methionine depletion in vivo, using the technique of total parenteral nutrition (TPN) by infusing an amino acid solution devoid of methionine and cysteine, as sole nitrogen source (Met-deplet. TPN). In Experiment 1, we demonstrated that the marked depletion of thiol was induced both in the liver and tumor tissues by Met-deplet. TPN in Sato lung carcinoma (SLC)-bearing rats. Then in Experiment 2, we also confirmed the presence of the enhancing effect on nimustine hydrochloride (ACNU) in Met-deplet. TPN to SLC. The tumor proliferation was inhibited significantly by Met-deplet. TPN even in conjunction with a small dose of ACNU, which showed no anti-tumor effect on the rats treated with methionine-containing amino acid solution, without apparent increase of the side effects in comparison with those in the control groups. On the other hand, to determine the carcinostatic effect on tumor-bearing animals, not only the size of the tumor but also its components, especially the percentage of necrotic tumor tissue (necrotic index), were considered to be important.
2. Synthesis of a novel L-methyl-methionine-ICG-Der-02 fluorescent probe for in vivo near infrared imaging of tumors
Didel M Mahounga, Lingling Shan, Cao Jie, Changli Du, Shunan Wan, Yueqing Gu Mol Imaging Biol. 2012 Dec;14(6):699-707. doi: 10.1007/s11307-012-0560-4.
Purpose: A novel near infrared fluorescent probe, L-methyl-methionine (Met)-ICG-Der-02, was synthesized and characterized for in vivo imaging of tumors and early diagnosis of cancers. Method: Met was conjugated with ICG-Der-02 dye through the amide bond function by ethyl-3-(3-dimethyllaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide catalysis chemistry. Met-ICG-Der-02 probe uptake was evaluated on PC3, MDA-MB-231, and human embryonic lung fibroblast cell lines. The dynamics of Met-ICG-Der-02 was investigated in athymic nude mice prior to evaluation of the probe targeting capability in prostate and breast cancer models. Results: Met-ICG-Der-02 was successfully synthesized. Cell experiments demonstrated excellent cellular uptake of Met-ICG-Der-02 on cancer cell lines without cytotoxicity. Optical imaging showed a distinguishable fluorescence signal in the tumor area at 2 h while maximal tumor-to-normal tissue contrast ratio was at 12 h Met-ICG-Der-02 post-injection. Additionally, dynamic study of the probe indicated intestinal and liver-kidney clearance pathways. Conclusion: Met-ICG-Der-02 probe is a promising optical imaging agent for tumor diagnosis, especially in their early stage.
3. Cytotoxic effects of methionine alkyl esters and amides in normal and neoplastic cell lines
M A Clement, J M Chapman, J Roberts J Pharm Sci. 1989 Jun;78(6):465-9. doi: 10.1002/jps.2600780609.
Homologous series of L-methionine alkyl ester hydrochlorides and tosylates were synthesized and evaluated for in vitro growth inhibitory activity in Meth A sarcoma. Cytotoxicity, as determined by [3H]thymidine incorporation, was found to be directly proportional to alkyl chain length and surface tension lowering activity. L-Methionine decyl and dodecyl ester hydrochlorides possessed optimum cytotoxic activity (IC50 = 29, 28 microM) which was not reversible by the addition of L-methionine. Surface tension of a 50 microM solution of the decyl and dodecyl ester hydrochlorides were 35.4 and 32.7 dyn/cm, respectively. The corresponding decyl and dodecyl ester tosylates and amide hydrochlorides were less active. The N-t-butoxycarbonyl analogues were essentially inactive, demonstrating the necessity of an unsubstituted and/or potentially cationic amino group. Methionine dependence characteristics and cytotoxicity were also determined for three human (IMR-90, LX-1, MCF7) and four additional murine (L1210, L5178Y, 3T3, SV-T2) cell lines. The human cell lines Meth A, LX-1, and SV-T2 were found to be methionine independent. The LX-1 tumor cell line and the SV-T2 transformed line exhibited two to four times more sensitivity to the cytotoxic and cytolytic properties of the decyl and dodecyl ester hydrochlorides than their normal counterparts. The dodecyl amide hydrochloride derivative demonstrated enhanced cytotoxic activity in vivo relative to the corresponding ester, possibly due to decreased metabolic hydrolysis.
