Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the effects of WR-2721 and its metabolite WR-1065 on in vitro growth inhibition by 5-fluorouracil (5FU) and cisplatin (CDDP) and the effect of WR-2721 on in vivo toxicity and antitumor effect of 5FU and CDDP. In cell culture both WR-2721 and WR-1065 were not able to reverse growth inhibition caused by either 5FU or CDDP. Administration of WR-2721 i.p. at 525 mg/kg to mice resulted in a severe temperature drop to 27 degrees C; at 200 mg/kg hypothermia was less severe. WR-2721 failed to prevent 5FU toxicity, but the maximum tolerated dose of CDDP in the combination with 5FU (at 100 mg/kg) could be increased from 3 to 7 mg/kg. CDDP at 7 mg/kg enhanced leukopenia caused by 5FU at 100 mg/kg to 20% and thrombocytopenia to 40%; WR-2721 reduced leukopenia and prevented thrombocytopenia induced by the combination. Combination of CDDP, 5FU, and WR-2721 resulted in an enhanced antitumor activity against the murine colon tumor Colon 26 compared to 5FU alone and to 5FU combined with CDDP at their maximum tolerated dose.
 ...
PMID:Protection by WR-2721 of the toxicity induced by the combination of cisplatin and 5-fluorouracil. 131 75

Ionizing radiation induces hypothermia in guinea pigs. While systemic injection of the radioprotectant S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) did not block hyperthermia induced by exposure to 10 Gy of gamma radiation, central administration did attenuate it. The dephosphorylated metabolite of WR-2721, N-(2-mercaptoethyl)-1,3-diaminopropane (WR-1065), accentuated radiation-induced hypothermia by both routes of administration. In brain homogenates, oxygen uptake was inhibited by WR-2721 but elevated by WR-1065. These results suggest that the antagonism of radiation-induced hypothermia found only after central administration of WR-2721 is due to its direct actions and not to its dephosphorylated metabolite and that this effect may be correlated with the inhibition by WR-2721 of oxygen uptake.
 ...
PMID:Opposite effects of WR-2721 and WR-1065 on radiation-induced hypothermia: possible correlation with oxygen uptake. 283 82

Amifostine (WR-2721, S-2 [3-aminopropylamino]-ethylphosphorothioic acid; Ethyol, US Bioscience, Inc. West Conshohocken, PA), developed as a radiation protector, has exhibited activity as a chemoprotector. The compound requires activation by dephosphorylation to produce the free thiol, WR-1065. This process is catalyzed by capillary alkaline phosphatase that is close to the desired site of protection. Additionally, the neutral pH of normal tissues, compared with the slightly acidic pH of tumors, favors selective activation. The protective mechanism against radiation damage is produced, and is, most probably, different from that of chemotherapy. The most likely mechanism for radioprotection involves free radical scavenging and hydrogen donation to repair damaged DNA. The hydrogen ion donation by the thiol group is required for both chemoprotection and radioprotection. Chemoprotection is presumed to be mediated by inactivation of the charged carbonium ions of activated alkylating agents through a nucleophilic attack, thereby protecting the nucleic acids from alkylation. Amifostine is able to reduce DNA platination when preincubated or coincubated with cisplatin, but this effect is much weaker when given postincubation. Observations show that maximum protection can only be obtained if amifostine is given before the administration of cytotoxic therapy. Amifostine side effects, as seen in mice, are dose dependent. A dose of 200 mg/kg has been found to be relatively nontoxic, although some hypothermia was observed.
 ...
PMID:Protection of normal tissues from the cytotoxic effects of chemotherapy and radiation by amifostine (Ethyol): preclinical aspects. 797 74