Pharmacokinetics and metabolism of a new antitumor semisynthetic ether phospholipid, 14C-labeled plasmanyl-(N-acyl)ethanolamine, in mice bearing sarcoma Mc11.

New natural and semisynthetic antitumor ether phospholipids PNAE and PNAE(s) [plasmanyl-(N-acyl)ethanolamines] and their selective antitumor activity in vivo have been described previously. We are now presenting the pharmacokinetics, in vivo metabolism and distribution of a [14C]PNAE(s) preparation (1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-[U-14C]palmitoyl) ethanolamine in the intact or Mc11-tumor-bearing BDF1 mice. Only partial degradation (about 50%-60%) of [14C]PNAE(s) was observed in vivo 24 h after i.v. administration, as detected by TLC analysis of phospholipids extracted from the blood, liver, tumor and brain of animals. Pharmacokinetic curves of [14C]PNAE(s) and its metabolites were fitted with a two-compartment model (t alpha 1/2 = 2.5 h, t beta 1/2 = 61.6 h). After repeated i.v. doses of [14C]PNAE(s) (administered on days 1, 2, 3, 4, and 5) accumulation of [14C]PNAE(s) and lyso-[14C]PNAE(s) in tumor tissue was detected. High levels of [14C]PNAE(s) were also detected in the liver, lung and spleen of animals. After i.v. administration of [14C]PNAE(s) the ether phospholipid was also detected in the brain tissue. The parmacokinetic data indicate that repeated parenteral doses of PNAE(s) are necessary to attain therapeutic concentrations in tumor tissue. The very high accumulation of [14C]PNAE(s) in the liver of animals after repeated i.v. doses, and the absence of toxic side-effects in vivo indicate a possible clinical therapeutic use of PNAE(s), especially in the treatment of tumor metastases in liver as well as in the prophylaxis of liver metastases after surgical removal of primary tumors.

[Separation of natural ribonucleoside triphosphates and their determination in an acid-soluble cell fraction by anion exchange high performance liquid chromatography]. / Razdelenie prirodnykh ribonukleozidtrifosfatov i ikh opredelenie v kislotorastvorimoi fraktsii kletok metodom anionoobmennoi zhidkostnoi khromatografii vysokogo razresheniia.

An anion-exchange HPLC procedure for CTP, UTP, ATP and GTP determination in the acid-soluble fraction of cells is described. Ribonucleoside triphosphates are separated on LiChrosorb AN isocratically with NH4H2PO4-acetonitrile. The dependence of the separation efficiency on the salt and acetonitrile concentrations and pH was analyzed and the optimal conditions were chosen. The range, wherein the linearity between the ribonucleoside triphosphate amount and the area of the corresponding peak is observed, was defined and the regression equations were derived. The CTP, UTP, ATP and GTP content in the ovarian cancer cells CaOv in culture was found to be 418 +/- 32, 1122 +/- 21, 9262 +/- 442 and 1036 +/- 49 pmole/10(6) cells, respectively. After 2 hr incubation with 6-mercaptopurine (10(-4) M) the level of ATP and GTP is reduced by 55%, and after 24 hr incubation--by 73% for ATP and 85% for GTP. At the same time the UTP and CTP content is decreased by 12-31%.

[A novel immunoregulating hexapeptide with antineoplastic effect]. / Novyi immunoreguliatornyi geksapeptid s protivoopukholevym deistviem.

A synthesized analog of myelopeptide HP-2-->M[symbol: see text]-2 (Leu-Val-Val-Tyr-Pro-Trp) caused a significant (60-80%) and prolonged inhibition of s.c. grafted tumors P388, Ca-755, B-16 and sarcoma 180 in isogenic mice but did not affect the growth of tumor B-16 in nude mice. Nor did it influence proliferative activity or viability of cultured human tumor cells. The best results were obtained with s.c. injections of 0.5-2 mg/kg HP-2-->M[symbol: see text]-2, twice or trice a day, at 96 hr intervals. No symptoms of severe poisoning were registered at doses of HP-2-->M[symbol: see text]-2 100 times the therapeutic one. A pharmacokinetic study in mice revealed prolonged circulation of HP-2-->M[symbol: see text]-2 in blood and a high affinity for the bone marrow (t 1/2 (130.1 hr and 431.6 hr, respectively). HP-2-->M[symbol: see text]-2 restored in vitro the ascites P388-suppressed cytotoxicity of murine T-lymphocytes. HP-2-->M[symbol: see text]-2 is regarded as a candidate for clinical studies of its potential of immunocorrection in cancer patients suffering T-lymphocyte immunity disturbances.

[Results of a phase I clinical trial of "theraphthal + ascorbic acid" catalytic system]. / Rezul'taty I fazy klinicheskogo izucheniia kataliticheskoi sistemy "teraftal + askorbinovaia kislota".

Phase-I clinical studies of teraphtal and a "teraphtal + ascorbic acid" catalytic system have been completed. The dose-limiting toxicity and maximum tolerable dose were not reached even at the end of maximal dose trials. No side-effects characteristic of antitumor cytostatic drugs were registered. The gravest side-effect ever recorded was a collapse which could not be linked to teraphtal dosage and was probably caused by hypersensitivity to the drug. The drug was recommended for phase II trials.