Disease relevance of Gammaphos

• We investigated the causes of the hypocalcemia associated with WR-2721, an investigational drug that protects normal tissues against the toxic effects of radiation and chemotherapy [1].
• WR-2721 could therefore be an effective drug to treat human hypercalcemia of malignancy, particularly in those tumors wherein a markedly enhanced renal Ca reabsorption contributes to the elevation of the plasma Ca level [2].
• Bone resorption by primary culture of chick osteoclasts was inhibited by WR 2721 at concentrations as low as 10(-4) M in the absence of hormonal stimulation [3].
• Intracolonic WR 2721 protection of the rat colon from acute radiation injury [4].
• These data demonstrate that WR 2721 exerts its radioprotective effect without the coincident development of secondary tissue hypoxia and provide rationale for a clinical trial in humans [4].

Psychiatry related information on Gammaphos

• WR 2721 produced lethargy, unsteady gait, and dishevelment but these signs all resolved completely within 1-3 days in survivors [5].
• In the first study, rats trained on the accelerod motor performance task were give 200, 300, or 400 mg/kg WR-2721 intraperitoneally (ip) [6].
• Dose and time relationships of the radioprotector WR-2721 on locomotor activity in mice [7].

High impact information on Gammaphos

• We conclude that WR-2721 inhibits the secretion of parathyroid hormone and enhances calciuria, thereby leading to hypocalcemia [1].
• These results suggest that in this HHM model, WR-2721 can normalize calcemia through its PTH-independent inhibitory effect on TRCa [2].
• (b) In intact rats a maximal hypocalcemic dose of WR-2721 reduced urinary cyclic AMP excretion from 70.5 +/- 6.3 to 38.2 +/- 3.1 pmol/ml glomerular filtration rate (GFR), a level comparable to that observed (35.9 +/- 5.2 pmol/ml GFR) in thyroparathyroidectomized (TPTX) rats [8].
• After several days of saline diuresis the patient received WR-2721, 740 mg/m2 over 15 minutes, resulting in a fall in serum calcium from 11.76 to 9.06 mg/dL within 24 hours [9].
• It is concluded that if WR-2721 is capable of selectively protecting nontumor tissue from the toxicities of platinum-based chemotherapy, it is doing so by some mechanism other than its selective uptake into normal tissue and subsequent nonspecific inactivation of any reactive cytosolic platinum species formed [10].

Chemical compound and disease context of Gammaphos

• The radioprotective thiophosphate compound WR 2721, when given intraperitoneally, has been shown to effectively protect normal murine tissues, but not tumors, from radiation injury [4].
• WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma [11].
• In no instance did the prior administration of WR-2721 diminish the bone marrow toxicity of cyclophosphamide alone [12].
• Effect of the chemoprotective agent WR-2721 on disposition and biotransformations of ormaplatin in the Fischer 344 rat bearing a fibrosarcoma [10].
• Purging of small cell lung cancer cells from human bone marrow using ethiofos (WR-2721) and light-activated merocyanine 540 phototreatment [13].

Biological context of Gammaphos

• Plasma protein binding of ormaplatin was decreased by 50% in the presence of WR-2721 [10].
• Pharmacokinetics of WR-2721 [14].
• Protection from progressive renal failure and hyperparathyroid bone remodeling by WR-2721 [15].
• WR-2721 increased the survival of mice; the PF calculated from the LD50 values was 1 [16].
• WR 1065 protected U937 cells from H2O2-induced cell death in a dose-dependent manner, and more efficiently than WR 2721 [17].

Anatomical context of Gammaphos

• S-2-(3-Aminopropylamino)ethylphosphorothioic acid, commonly known as WR-2721, is a radioprotective drug which has been shown to protect against bone marrow depression in irradiated humans [18].
• With WR-2721 pretreatment, 19 of 21 (90%) patients had improved WBC and granulocyte counts [19].
• S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) was investigated for its protective effect against radiation-produced damage of jejunum, testis, lung, hair follicles, and a fibrosarcoma of C3Hf/Kam mice [20].
• In Chinese hamster ovary (CHO) and Chinese hamster ovarian carcinoma (OvCa) cells, WR-2721 exposure alone did not increase the cystine uptake relative to that of control (untreated) cells, while WR-2721 + AP enhanced the uptake of cystine more than twofold in both cell lines [21].
• The proportion of macrophages in tumors growing in WBI mice was significantly reduced, but not when WR-2721 was first given [22].

Associations of Gammaphos with other chemical compounds

• In order to convert WR-2721 to the free thiol compound (WR-1065) in vitro, the medium also contained 20 U/ml alkaline phosphatase (AP) [21].
• In vitro metabolism of the phosphorothioate radioprotectors WR-2721 and WR-3689 [23].
• Amifostine (WR-2721) is a cytoprotective agent that protects a broad range of normal tissues from the toxic effects of chemotherapy and radiotherapy without attenuating tumour response [24].
• Three weeks after systemic administration of 16-16 dm PGE2 (Upjohn Company) or WR-2721, given 1 h before each dose of 2-4.5 Gy per fraction for 10-15 fractions, regrowing hair counts increased up to 100% compared to irradiated-only skin sites [25].
• Cisplatin "rescue" was demonstrated by DDTC, WR-2721 and 5-TG, and enhanced effects on the inhibition of tumor growth resulted when 20 mg/kg cisplatin and 730 mg/kg DDTC were combined with radiotherapy [26].
• The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from the plasma data were 107 L/h/m(2), 5.53 L/m(2), and 30.6 L/h/m(2) [27].

Gene context of Gammaphos

• In contrast, the abundance of IAP expression in normal tissues, stromal and vascular, ensures an intense hydrolysis of WR-2721 and rapid intracellular accumulation of WR-1065 [28].
• In incubations with fetal rat long bone labeled in utero with 45Ca, 10(-3) M WR 2721 inhibited PTH-stimulated, but not base-line release of 45Ca [3].
• Several approaches to decrease the myelotoxicity of chemo- and/or radiotherapy were discussed: MDR gene therapy, use of chemical compounds (AS101, WR 2721), cytokines such as TNF alpha and IL-1 and small peptides, pEEDCK and AcSKDP [29].
• Plasma concentrations of three other hormones, i.e. renin, insulin, and prolactin, were not affected by the administration of WR-2721 [30].
• PURPOSE: This study tests the hypothesis that p53 status, i.e. wild type versus mutant form, is a determinant in radiation protection of human glioma cells by WR-1065, the active thiol form of amifostine (WR-2721) [31].

Analytical, diagnostic and therapeutic context of Gammaphos

• Intravenous injection of 30 mg/kg WR 2721 in rats and 15 mg/kg in dogs lowers serum calcium by 19 and 25%, respectively [3].
• The reverse-phase HPLC peak, which behaved chromatographically as a Pt(dach)(WR-1065) standard, was less prominent after the i.v. administration of WR-2721 than it was after i.p. administration under any of the paradigms tested [10].
• The results suggest that ethiofos sensitized SCLC cells to LAMP; thus ethiofos-enhanced LAMP may be an effective method for removing metastatic SCLC cells from bone marrow used for autologous marrow transplantation after high dose chemotherapy [13].
• We sought to determine if WR-2721 would decrease bone loss in an animal model of disuse osteoporosis produced by unilateral knee tenotomy in the rat [32].
• The ability of WR-2721 to prevent radiation-induced immunosuppression, metastatic spread, and carcinogenesis are additional benefits in the therapeutic use of this agent [33].

References