The efficacy and safety of amifostine for the acute radiation syndrome

Figures & data

Figure 1. The radioprotective domain of phosphorothioate.

Table 1. Indications for which amifostine has received full FDA approval.

Indications	FDA approval	Dose	Treatment schedule	Caution
For reduction of cumulative renal toxicity with cisplatin chemotherapy of patients with ovarian cancer	1996	910 mg/m^2	Administered once daily as a 15-min iv infusion, starting 30 min prior to chemotherapy	Adequately hydrated prior to the infusion and kept in a supine position during the infusion, blood pressure should be monitored every five min during the infusion and thereafter as clinically indicated.
For reduction of moderate to severe xerostomia from irradiation of the head and neck	1999	200 mg/m^2	Administered once daily as a 3-min iv infusion, starting 15–30 min prior to standard fraction radiation therapy (1.8–2.0 Gy)	Adequately hydrated prior to the infusion, blood pressure be monitored at least before and immediately after the infusion, and thereafter as clinically indicated, antiemetic drug (5-HT3 receptor antagonists, alone or in combination with other antiemetics) be administered prior to and in conjunction with amifostine.

The above details are based on the amifostine label for injection [39]. 5-HT3; a serotonin receptor

Figure 2. Simplified diagram for the mechanism of action of amifostine. Amifostine protects against radiation/chemotherapeutic agent-induced DNA damage. It has anti-mutagenic, anti-carcinogenic characteristics, affect redox-sensitive transcription factors, gene expression, chromatin stability, enzymatic activity, affects growth and cell cycle progression, and prevents the up-regulation of inflammatory pathways.

Table 2. Radioprotective efficacy of amifostine (WR-2721) in mice.

Dose (mg/kg)	DRF		References
	H-ARS	GI-ARS
500	2.70	1.80	^[Citation48]
500	-	1.64	^[Citation49]
400	2.25	-	^[Citation50]
365	2.29	1.55	^[Citation51]

Table 3. Radioprotective efficacy of selected agents.

Name	Chemical Structure	Dose MTD/2 (mg/kg)	DRF
			Hematopoietic protection (30 min interval)	Gastrointestinal protection (30 min interval)	Pulmonary syndrome (180 days lethality)
WR-638	H2N-(CH2)2-S-PO3H2	450	1.91	1.30	1.29
WR-77,913	H2N-CH2-CHOH-CH2-S-PO3H2	900	1.86	1.24	1.29
WR-2721	H2N-(CH2)3-NH-(CH2)2-S-PO3H2	365	2.29	1.55	1.36
WR-3689	CH3-HN-(CH2)3-NH-(CH2)2-S-PO3H2	450	2.22	1.51	1.31
WR-44,923	H2N-(CH2)3-NH-(CH2)3-S-PO3H2	207	1.70	1.63	1.28
WR-151,327	CH3-HN-(CH2)3-NH-(CH2)3-S-PO3H2	315	1.93	1.40	1.27

Drugs were injected ip into BALB/c mice at half the maximum tolerated dose 30 min prior to irradiation [27]. These agents were also tested in some large animal models (canine, minipig, and NHP) [26]. WR3721 was found to be superior compared to other agents and its data with large animal models are presented in Table 4.

Table 4. Radioprotective efficacy of amifostine (WR-2721) in rodent, canine, and NHP.

Species	Radiation Dose (Gy)	Drug Dose (mg/kg)	Route of Administration	Time (h)	Percent Survival
Mice	8.25 (X-ray)	600	ip	0.25	100
		300			100
		150			100
		75			80
		50			10
		0			0
		600		0.5	86
				1	100
				1.5	93
				2	100
				3	93
		0		-	0
		700	po	1	90
				2	60
				3	50
		0		-	0
	9.5 (γ-photon)	700	po	2	87
				3	67
				4	13
				5	0
		0		-	0
Canine	4.5 (X-ray)	200	iv	0.5	100
		0		-	0
	6.5 (γ-photon)	150	iv	0.5	50
		0		-	0
NHP	10 (γ-photon)	250	iv	0.5	100
		0		-	0
		300	po	0.5	0
		0		-	0

The MTD and LD₅₀ with ip route in mice were 600 mg/kg and 950 mg/kg, respectively [26].

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