Pii: s0167-8140(00)00235-8

Radiotherapy and Oncology 57 (2000) 113±118 Has the outlook improved for amifostine as a clinical radioprotector? Department of Oncology, Aarhus University Hospital, Nùrrebrogade 44, DK-8000 Aarhus C, Denmark Received 26 November 1999; received in revised form 24 February 2000; accepted 9 May 2000 Amifostine has recently been approved for clinical radiotherapy as a protector against irradiation-induced xerostomia. It is our aim to review the outlook for using amifostine as a general clinical radioprotector.
Protection against X-rays is mainly obtained by the scavenging of free radicals. The degree of protection is therefore highly dependent on oxygen tension, with protection factors ranging from 1 to 3. Maximal protection is observed at physiological levels of oxygenation. A great variability in protection has also been observed between different normal tissues. Some tissue, like brain, is not protected while salivary glands and bone marrow may exhibit a three-fold increase in radiation tolerance. Amifostine is dephosphorylized to its active metabolite by a process involving alkaline phosphatase. Due to lower levels of alkaline phosphatase in tumor vessels, amifostine is marketed as a selective protector of normal tissue and not tumors. However, the preclinical investigations concerning the selectivity of amifostine are controversial and the clinical studies are sparse and do not have the power to evaluate the in¯uence of amifostine on the therapeutic index. Conclusion: based on the present knowledge amifostine should only be used in experimental protocols and not in routine practice. q 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Amifostine; Radioprotector; Selectivity a selective protection of normal tissue from damage induced not only by irradiation, but also from chemotherapy [64,65].
More than 50 years ago, it was realized that radiation- During the 1980s, clinical phase I±II studies showed that induced inactivation of biological substances could be the use of amifostine was feasible, and that amifostine modulated by certain amino acids, glutathione and ascorbic seemed to protect normal tissue from both ionizing irradia- acid. Based on these observations, Patt et al. [35] studied the tion and chemotherapy. Based on a phase III trial published effect of treating rats with the thiol containing amino acid, in 1996, amifostine was registered by the Food and Drug cysteine, before 8 Gy total body irradiation (Fig. 1). A Administration (FDA) for use as a cytoprotective agent with remarkable increase in survival was observed. In contrast, cisplatin based chemotherapy against ovarian cancer [22].
no effect was observed when cysteine was given after irra- Recent data, indicating that amifostine may be used to diation. The authors concluded that the ameliorating effect prevent xerostomia in patients treated with radiotherapy could reside in the protection afforded by certain critical for head and neck cancer [4], has led the FDA to extend cellular constituents against oxidation by the presence of the approval to this indication as well.
Despite the FDA approval and an increasing number of In a political climate of cold war, these ®ndings obviously positive reviews published during recent years [7± had immense importance and led to a large research 9,21,51,60,61], the selectivity of amifostine remains contro- program at the Walter Reed Army Institute of Research in versial. In our opinion, many of these recent reviews are the US [19]. Numerous sulfhydryl containing substances incomplete and do not suf®ciently discuss the problem of with substantial radioprotective properties were tested, but tumor protection. The pitfalls in clinical trials using amifos- only the agent WR-2771 (amifostine) was found to exhibit tine as a protector against chemotherapy-induced toxicities an acceptable toxicity. The idea of using amifostine in were recently thoroughly reviewed by Phillips and Tannock oncology was then fueled by preclinical studies suggesting [38]. It is our aim to reappraise an old correspondence [13,66] and give an updated, independent and critical commentary on the outlook for using amifostine as a clinical 0167-8140/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved.
J.C. Lindegaard, C. Grau / Radiotherapy and Oncology 57 (2000) 113±118 organ in radiotherapy, is not protected at all, since amifos- tine does not cross the blood±brain barrier [31,59]. In other tissues, the protection factors range from 3 (hematopoietic system and salivary glands) to near 1 (lung, kidney and bladder) [2,42,45,53,69]. Even within one tissue, a wide range of protection factors have been reported [33,42].
These variations may to some extend be explained by varia- tions in oxygen concentration and dephosphorylation activ- ity [33]. Large differences in the decline of WR-1065 tissue concentration within 15±30 min [57], which is the normal time interval between administration of amifostine and radiotherapy, may also explain these differences.
There is substantial evidence to suggest that oxygen concentration varies considerably in normal tissues, and that this variation in oxygen concentration is, in fact, quan- titatively more important than the drug concentration of amifostine and its metabolites with respect to the degree of radioprotection obtained [33,53,69]. However, non- homogenous distribution of amifostine and its metabolites within each tissue [69], even at the level of the DNA [46], Fig. 1. Data from Patt et al. [35] showing the effect of 1/2 pretreatment with 575 mg cysteine i.v. on survival in Sprague±Dawley rats exposed to may also contribute to this heterogeneity.
800 Roentgens total body irradiation.
2. Mechanisms and magnitude of radioprotection 3. Preclinical data on tumor protection and therapeutic Amifostine is dephosphorylized to its active metabolite, WR-1065, either by spontaneous non-enzymatic hydrolysis In contrast to its dephosphorylated analogue, WR-1065, at low pH, or by a catalyzed process involving alkaline phos- amifostine is a very hydrophilic drug and does not readily phatase with a pH optimum at 8±9 [47]. WR-1065 is further cross the cell membranes [65]. Studies with radiolabeled metabolized to the disul®de, WR-33278, that also may afford drugs injected into mice have shown that amifostine is some protection, though to a much lesser extent [37,46].
rapidly cleared from plasma within a few minutes, and Several protection mechanisms are involved depending on that shortly thereafter, WR-1065 accumulates in high the quality of the radiation. Protection against sparsely ioniz- concentrations in most normal tissues and in markedly ing radiation such as X-rays is mainly obtained by the scaven- ging of free radicals [12,19,53]. Since WR-1065 and WR- 33278 react with free radicals in competition with oxygen, the protection obtained by scavenging is highly in¯uenced by oxygen tension (Fig. 2). The protection is maximal at inter- mediate levels of oxygen (20±50% oxygen in the inspired air) [12]. At higher oxygen tensions, WR-1065 is outbalanced by excess oxygen and the protection is gradually lost. The degree of protection is also diminished at low oxygen tensions where the scavenging of free radicals becomes less and less important as the lack of oxygen by itself provides radioprotection. Thiols may also react directly with oxygen and protect the cell by creating local hypoxia at the target [16]. Additional and complex mechanisms are undoubtedly involved. Some of these may involve chemical repair by donation of hydrogen [15], and decreased accessibility of radiolytic attack sites by induction of DNA packaging [46].
These mechanisms may yield oxygen independent protection and explain the protection observed with densely ionizing Quantitatively, there is great variability in the protection Fig. 2. Variations in radioprotection of mouse skin obtained with amifostine at different percentages of oxygen in the inspired air during irradiation with obtained both within and between different normal tissues.
electrons in vivo. Maximal radioprotection was observed with 21±50% The central nervous system, which often is the dose limiting oxygen. Redrawn from Denekamp et al. [12].
J.C. Lindegaard, C. Grau / Radiotherapy and Oncology 57 (2000) 113±118 lower concentrations in tumor tissue [47,57,64]. Studies in cells. In fact, most studies in mice have been performed humans, using a methodology that is more speci®c, have with relatively big tumors exposed to large single doses of con®rmed that amifostine is rapidly cleared from the irradiation. The preclinical results may therefore underesti- blood stream [47]. Based on these studies, a hypothesis mate the degree of tumor protection, which might be has been formed claiming that the lower activity of alkaline obtained with fractionated irradiation in a clinical dose phosphatase in tumor capillaries compared to blood vessels range where reoxygenation is signi®cant [45].
in normal tissue ensures a selective uptake of WR-1065 into Having accepted the existence of amifostine-induced normal cells [6]. Thus, amifostine is an inactive pro-drug, tumor protection, it is necessary to review the selectivity which is dephosphorylated to its active metabolite only in of the pro-drug hypothesis. This hypothesis has recently the normal tissue, thereby securing selective protection of been tested directly by studying the effect of amifostine normal tissues. The selective protection may be even on biotransformation and distribution of the platin analogue enhanced by the often acidic environment of tumor cells ormaplatin in Fischer rats bearing a ®brosarcoma in vivo causing inhibition of WR-1065 uptake [6].
[52]. Using an intraperitoneal injection of amifostine 30 min Based on this hypothesis and selected preclinical data, it prior to an intraperitoneal injection of ormoplatin, it was has often been maintained that amifostine-induced tumor found that amifostine was dephosphorylated and directly protection against the effect of irradiation is non-existent inactivated the chemotherapeutic agent in the peritoneal or negligible [7,21,37,61]. However, as reviewed by Dene- cavity. However, even when amifostine was given intrave- kamp [13] there are numerous papers reporting signi®cant nously 30 or 5 min before intraperitoneal injection of ormo- tumor protection with protection factors as high as 2.8 platin, there was no evidence of selective uptake of WR- [11,24,30,34,39,43,58,63,67,68]. Additional data published 1065 or selective ormoplatin inactivation in normal tissues.
later have also shown evidence for tumor protection, not These results seriously question the positive effect of only in rodents [27±29,36,40,44,45,62], but also in a rando- amifostine on the therapeutic index previously reported in mized study with 73 canine soft tissue sarcomas treated with preclinical studies with chemotherapy, where protection de®nitive radiotherapy [25]. As demonstrated in Fig. 3, the against platinum-induced toxicity was tested using intraper- percentage of tumor control was lower at all comparable itoneal injection of both amifostine and chemotherapy for dose levels in dogs pretreated with amifostine. In contrast, the normal tissue experiments while the chemotherapy was there was no evidence for amifostine protecting against given intravenously in the tumor experiments [54,55].
These data are often ignored [61], declared clinically irrelevant [51], or explained as being caused by artifacts [7,37]. Indeed, certain mice strains may develop hypother- mia and hypotension following injection of amifostine [7], Despite the fact that amifostine had been known for which could very well explain the tumor protection observed with chemotherapy using relatively large doses of amifostine [56]. In addition, hypotension may increase tumor hypoxia and thereby induce direct radioresistance [10]. In this context, it is important to remember that even light and transient hypotension, a well-known clinical side effect of amifostine, may, in fact, cause clinically relevant radioprotection [10,14], thereby canceling any selective distribution of WR-1065. However, tumor protection has also been observed in studies employing lower doses of amifostine [45,56], and in a range of mouse strains and other species [25] where these hemodynamic problems Thus, a number of factors may in¯uence the degree of protection observed in experimental tumors. Differences in the dose of amifostine, restraining method, tumor type, tumor size and endpoint may produce heterogeneous results [28,36,62]. Oxygen is important [53], with more protection being observed in small and well-oxygenated tumors compared with larger hypoxic tumors [28]. Differences in total dose and fractionation of radiotherapy are also impor- tant, with less tumor protection observed with large single Fig. 3. Tumor control at 1 year for dogs with soft tissue sarcomas treated doses [13,39,44,45,58]. In this situation, the response is with radiotherapy alone (XRT) or amifostine and radiotherapy dominated by the irradiation effect on the hypoxic tumor (XRT 1 WR2721). Redrawn from McChesney et al. [25].
J.C. Lindegaard, C. Grau / Radiotherapy and Oncology 57 (2000) 113±118 decades, very few clinical studies have been performed different (56%) between the two arms with a median follow- addressing the in¯uence of amifostine on the therapeutic up of 15 months. In 5/13 cases, amifostine was stopped due to index. Most studies have been retrospective of nature or tolerance problems. A randomized study from Argentina phase I±II [61]. In addition, chemotherapy has often been with combined radiation and chemotherapy for head and applied together with radiotherapy, making it dif®cult to neck cancer was stopped prematurely [18]. The investigators had hoped for a reduction in chemotherapy- and radiation- For pelvic radiotherapy, a retrospective analysis of 83 induced mucositis with the use of amifostine. This was not patients with cancer of the cervix did not show any radio- observed. In addition, the rate of tumor control was signi®- protective effect of amifostine (75 mg/m2) with regard to cantly reduced in the amifostine arm.
either tumor control or late normal tissue [32]. This lack of The ®nal report from a larger multi-center trial, with protection has been explained by the low amifostine dose participation from North America, Germany and France, received by most patients [51]. However, a dose-effect recruiting 315 patients in the period 1995±1997 is now avail- curve for radioprotection in humans has never been estab- able [4]. Patients received de®nitive or adjuvant radiation lished. One phase III trial with amifostine and radiotherapy therapy with daily fractions of 1.8±2.0 Gy to a total dose of in rectal cancer has been published [23]. One hundred 50±70 Gy 1/2 amifostine administered daily at a dose of patients with inoperable or recurrent cancer of the rectum 200mg/m2 30 min prior to radiation. There was no signi®cant were randomized between radiation alone or amifostine plus difference in the incidence of acute mucositis between treat- radiotherapy. The paper concluded that amifostine did not ment groups. However, amifostine signi®cantly reduced induce tumor protection and signi®cantly reduced the inci- moderate to severe acute xerostomia from 78 to 51%. At dence of late effects. However, as pointed out by Tannehill 1 year, the incidence of late xerostomia was also signi®cantly [51], there are several problems which invalidate the reduced in those patients who received amifostine (57 vs.
conclusions. The radiation dose was not the same in all 34%) and signi®cantly more patients had preserved saliva patients, and some patients were given chemotherapy production. Data for other late normal tissue endpoints was following radiotherapy in a non-randomized manner.
not reported. Analysis at the 18-month follow-up show no Many patients had previous pelvic surgery or went on to signi®cant difference in loco-regional tumor control (58 vs.
have tumor resection after radiotherapy. Finally, actuarial 64%), disease-free survival (63 vs. 64%), or over all survival methods are imperative to estimate the true incidence of late (81 vs. 73%) for patients treated with or without amifostine, radiation damage in a population with high mortality.
respectively. However, short follow-up time, a relatively In head and neck, a few trials have been conducted to test small number of patients and the use of surgery in two-thirds the ability of amifostine to protect against mucositis and of the patients hinder the evaluation of the in¯uence of xerostomia. In 1994, McDonald et al. [26] showed that amifostine, in a dose of 100 mg/m2, administered with each It is possible that the extreme radiosensitivity of the fraction of de®nitive radiotherapy given over 6±7 weeks, was serous acini [49,50], combined with a relatively high uptake tolerable and improved salivary gland function. Protection of and retention of amifostine and its metabolites in the paro- the salivary glands by amifostine in a dose of 500 mg/m2 was tids [37,64], represents a unique possibility for obtaining a also observed in a randomized study of 50 patients treated positive therapeutic index. Con®rmation of the study by with high-dose radioiodine treatment for thyroid cancer [1].
Brizel et al. [4] is therefore important and may eventually In a randomized trial, 39 patients received conventional result in a new strategy for morbidity reduction from xeros- radiotherapy (up to 60 Gy) with carboplatin, or the same tomia for patients treated with radical radiotherapy for head treatment with amifostine prior to treatment with carboplatin and neck cancer. Studies recruiting about 800 patients trea- [5]. There was a signi®cant reduction in the incidence of ted with de®nitive radiotherapy would be required to have severe mucositis, acute xerostomia and severe thrombocyto- suf®cient power to detect an estimated 5±10% decrease in penia in the amifostine arm. The incidence of xerostomia at local tumor control. Whether amifostine will show any 12 months was 17 (amifostine) vs. 55% (control), and the bene®t with regard to acute mucositis and late normal tissue incidence of loss of taste was 0 (amifostine) vs. 64% damage, like ®brosis, is presently unknown. These uncer- (control). There was no apparent difference in response tainties are also re¯ected in recent guidelines from the rates and disease-free survival at 12 months, but the statistical American Society of Clinical Oncology [20], as well as power of this study is so poor that no meaningful conclusion the approval by the FDA limiting the indications for amifos- can be drawn. The same problem was evident in a recent tine to prevention of xerostomia in patients undergoing post- phase II study from Institute Gustave Roussy in Paris [3].
operative radiation treatment for head and neck cancer [17].
Twenty-six patients with inoperable squamous cell carci- noma of the head and neck were treated with highly acceler- ated radiotherapy, giving 64 Gy in 3.5 weeks. Patients were randomized to 1/2 amifostine prior to each radiation session. Both the incidence and duration of severe mucositis In 1983, Denekamp [13] stated that `normal tissue radio- was reduced with amifostine. Loco-regional control was not protection is dif®cult to introduce because there is no fail J.C. Lindegaard, C. Grau / Radiotherapy and Oncology 57 (2000) 113±118 safe modi®cation of traditional radiotherapy'. Unfortu- randomized trial of amifostine as a radioprotectant in head and neck nately, the studies published since then have not changed cancer. Int J Radiat Oncol Biol Phys 1999;45(Suppl. 1):147±148.
this situation very much. If amifostine is to be used in [5] Buntzel J, Kuttner K, Frohlich D, Glatzel M. Selective cytoprotection combination with radiotherapy prescribed in the conven- with amifostine in concurrent radiochemotherapy for head and neck tional dose, it requires convincing data that tumor protection [6] Calabro-Jones PM, Fahey RC, Smoluk GD, Ward JF. Alkaline phos- will not occur. The preclinical studies have not been able to phatase promotes radioprotection and accumulation of WR-1065 in provide this evidence so far. In contrast, the data has shown V79-171 cells incubated in medium containing WR-2721. Int J Radiat that the asserted difference in alkaline phosphatase activity Biol Relat Stud Phys Chem Med 1985;47:23±27.
between tumor and normal tissue is unable to provide 100% [7] Capizzi RL. Amifostine: the preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies.
selective protection of normal tissues against the cytotoxic effect of chemotherapy [52]. In addition, variable degrees of [8] Capizzi RL. Clinical status and optimal use of amifostine. Oncology tumor radioprotection with a reduction of the biologically effective dose to the tumor of 0±25% have been observed [9] Capizzi RL, Oster W. Protection of normal tissue from the cytotoxic [13]. Recent clinical data in head and neck indicate a clin- effects of chemotherapy and radiation by amifostine: clinical experi- ical bene®t with regard to prevention of xerostomia [4].
ences. Eur J Cancer 1995;31A(Suppl. 1):S8±S13.
[10] Chaplin DJ, Horsman MR. Tumor blood ¯ow changes induced by Unfortunately, this study does not have suf®cient power to chemical modi®ers of radiation response. Int J Radiat Oncol Biol detect and quantify tumor protection. However, if a positive therapeutic index with regard to xerostomia is con®rmed in [11] Clement JJ, Johnson RK. In¯uence of WR 2721 on the ef®cacy of larger trials, a new treatment strategy in radical radiotherapy radiotherapy and chemotherapy in murine tumors. Int J Radiat Oncol for cancer of the head and neck may be at hand.
[12] Denekamp J, Michael BD, Rojas A, Stewart FA. Radioprotection of Escalation of radiation dose has been suggested [61], but mouse skin by WR-2721: the critical in¯uence of oxygen tension. Int this approach requires the protection of all normal tissues at J Radiat Oncol Biol Phys 1982;8:531±534.
risk. A major problem is the large range of protection factors [13] Denekamp J, Stewart FA, Rojas A. Is the outlook grey for WR-2721 observed in different normal tissues. Thus, a positive ther- as a clinical radioprotector? Int J Radiat Oncol Biol Phys 1983; apeutic index obtained with regard to some normal tissues, like the salivary glands, may be offset by a negative ther- [14] Dische S, Chassagne D, Hope-Stone HF, et al. A trial of Ro 03-8799 (pimonidazole) in carcinoma of the uterine cervix: an interim report apeutic index for the same treatment with regard to other from the Medical Research Council Working Party on advanced important normal tissues, like the spinal cord or ®brosis! carcinoma of the cervix. Radiother Oncol 1993;26:93±103.
Evidently, it is very important for any cytoprotective [15] Durand RE. Radioprotection by WR-2721 in vitro at low oxygen agent that it does not protect tumor cells; even more so, tensions: implications for its mechanisms of action. Br J Cancer when the dose escalation of irradiation is dangerous due [16] Durand RE, Olive PL. Radiosensitization and radioprotection by BSO to a variable, an unpredictable degree of normal tissue and WR-2721: the role of oxygenation. Br J Cancer 1989;60:517± protection. At present, it is therefore not recommendable to incorporate amifostine in routine radiotherapy practice.
[17] Food and Drug Administration. Ethyolw (amifostine) for injection, In our view, amifostine must still be considered an experi- [18] Giglio R, Mickiewitcz E, Pradier E, et al. Alternating chemotherapy (CT) 1 radiotherapy (RT) with amifostine (A) protection for head and neck cancer (HN). Early stop of a randomized trial. Abstract [19] Hall EJ. Radiobiology for the radiologist, 4th ed., Philadelphia, PA: This work has been supported by the Danish Cancer [20] Hensley ML, Schuchter LM, Lindley C, et al. American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol [21] Hospers GA, Eisenhauer EA, de Vries EG. The sulfhydryl containing compounds WR-2721 and glutathione as radio- and chemoprotective [1] Bohuslavizki KH, Klutmann S, Brenner W, et al. Salivary gland agents. A review, indications for use and prospects. Br J Cancer protection by amifostine in high-dose radioiodine treatment: results of a double-blind placebo-controlled study. J Clin Oncol 1998; [22] Kemp G, Rose P, Lurain J, et al. Amifostine pretreatment for protec- tion against cyclophosphamide-induced and cisplatin-induced toxici- [2] Bohuslavizki KH, Klutmann S, Jenicke L, et al. Radioprotection of ties: results of a randomized trial in patients with ovarian cancer. J salivary glands by S-2-(3-aminopropylamin)-ethylphosphorothioic (amifostine) obtained in a rabbit animal model. Int J Radiat Oncol [23] Liu T, Liu Y, He S, Zhang Z, Kligerman MM. Use of radiation with or without WR-2721 in advanced rectal cancer. Cancer 1992;69:2820± [3] Bourhis J, De Crevoisier R, Abdulkarim B, et al. A randomized study of very accelerated radiotherapy with and without amifostine in [24] Lowy RO, Baker DG. Effect of radioprotective drugs on the thera- advanced head and neck squamous cell carcinoma. Int J Radiat peutic ratio for a mouse tumor system. Acta Radiol Ther Phys Biol [4] Brizel DM, Wasserman TH, Strnad V, et al. Final report of a phase III [25] McChesney SL, Gillette EL, Dewhirst MW, Withrow SJ. In¯uence of J.C. Lindegaard, C. Grau / Radiotherapy and Oncology 57 (2000) 113±118 WR 2721 on radiation response of canine soft tissue sarcomas. Int J DNA against fast neutron-induced strand breakage. Int J Radiat Biol Radiat Oncol Biol Phys 1986;12:1957±1963.
[26] McDonald S, Meyerowitz C, Smudzin T, Rubin P. Preliminary results [47] Shaw LM, Bonner H, Lieberman R. Pharmacokinetic pro®le of of a pilot study using WR-2721 before fractionated irradiation of the amifostine. Semin Oncol 1999;23:18±22.
head and neck to reduce salivary gland dysfunction. Int J Radiat [48] Sigdestad CP, Connor AM, Scott RM. The effect of S-2-(3-aminopro- pylamino)ethylphosphorothioic acid (WR2721) on intestinal crypt [27] Mendiondo OA, Grigsby PW, Beach JL. Radioprotection combined survival. II. Fission neutrons. Radiat Res 1976;95:430±439.
with hypoxic sensitization during radiotherapy of a solid murine [49] Stephens LC, Schultheiss TE, King GK, Brock WA, Peters LJ. Target cell and mode of radiation injury in rhesus salivary glands. Radiother [28] Milas L, Hunter N, Ito H, Peters LJ. Effect of tumor type, size and endpoint on tumor radioprotection by WR-2721. Int J Radiat Oncol [50] Stephens LC, Schultheiss TE, Price RE, Ang KK, Peters LJ. Radiation apoptosis of serous acinar cells of salivary and lacrimal glands.
[29] Milas L, Hunter N, Reid BO. Protective effects of WR-2721 against radiation-induced injury of murine gut, testis, lung, and lung tumor [51] Tannehill SP, Mehta MP. Amifostine and radiation therapy: past, nodules. Int J Radiat Oncol Biol Phys 1982;8:535±538.
present, and future. Semin Oncol 1996;23:69±77.
[30] Milas L, Hunter N, Reid BO, Thames Jr HD. Protective effects of S-2- [52] Thomson DC, Wyrick SD, Holbrook DJ, Chaney SG. Effect of the (3-aminopropylamino)ethylphosphorothioic acid against radiation chemoprotective agent WR-2721 on disposition and biotransforma- damage of normal tissues and a ®brosarcoma in mice. Cancer Res tions of ormaplatin in the Fischer 344 rat bearing a ®brosarcoma.
[31] Millar JL, McElwain TJ, Clutterbuck RD, Wist EA. The modi®cation [53] Travis EL. The oxygen dependence of protection by aminothiols: of melphalan toxicity in tumor bearing mice by S-2-(3-aminopropy- implications for normal tissues and solid tumors. Int J Radiat Oncol lamino)-ethylphosphorothioic acid (WR 2721). Am J Clin Oncol [54] Treskes M, Boven E, Holwerda U, Pinedo HM, van der Vijg WJF.
[32] Mitsuhashi N, Takahashi I, Takahashi M, Hayakawa K, Niibe H.
Time dependence of the selective modulation of cisplatin induced Clinical study of radioprotective effects of amifostine (YM-08310, nephrotoxicity by WR2721 in the mouse. Cancer Res 1992; WR-2721) on long-term outcome for patients with cervical cancer.
Int J Radiat Oncol Biol Phys 1993;26:407±411.
[55] Treskes M, Boven E, van de Loosdrecht AA, et al. Effects of the [33] Mori T, Nikado O, Sugahara T. Dephosphorylation of WR-2721 with modulating agent WR-2721 on myelotoxicity and antitumour activity mouse tissue homogenates. Int J Radiat Oncol Biol Phys 1984; in carboplatin-treated mice. Eur J Cancer 1994;30A:183±187.
[56] Twentyman PR. Modi®cation by WR 2721 of the response to [34] Moulder JE, Lo PS, Fischer JJ. Effect of the radioprotective drugs chemotherapy of tumours and normal tissues in the mouse. Br J MEA, DMSO, and WR-2721 on tumor control and skin tolerance in the rat. Cancer Treat Rev 1977;61:825±833.
[57] Utley JA, Seaver N, Newton GL, Fahey RC. Pharmacokinetics of [35] Patt HM, Tyree EB, Straube RL, Smith DE. Cysteine protection WR-1065 in mouse tissue following treatment with WR-2721. Int J against X-irradiation. Science 1949;110:213±214.
Radiat Oncol Biol Phys 1984;10:1525±1528.
[36] Penhaligon M. Radioprotection of mouse skin vasculature and the [58] Utley JF, Phillips TL, Kane LJ, Wharam MD, Wara WM. Differential RIF-1 ®brosarcoma by WR-2721. Int J Radiat Oncol Biol Phys radioprotection of euoxic and hypoxic mouse mammary tumors by a thiophosphate compound. Radiology 1974;110:213±216.
[37] Peters GJ, van der Vijg WJF. Protection of normal tissues from the [59] Washburn LC, Rafter JJ, Hayes RL. Prediction of the effective radio- cytotoxic effects of chemotherapy and radiation by amifostine (WR- protective dose of WR-2721 in humans through an interspecies tissue 2721): preclinical aspects. Eur J Cancer 1995;31A:S1±S7.
distribution study. Radiat Res 1976;66:100±105.
[38] Phillips KA, Tannock IF. Design and interpretation of clinical trials [60] Wasserman T. Radiotherapeutic studies with amifostine (ethyol).
that evaluate agents that may offer protection from the toxic effects of cancer chemotherapy. J Clin Oncol 1998;16:3179±3190.
[61] Wasserman T. Radioprotective effects of amifostine. Semin Oncol [39] Phillips TL, Kane L, Utley JF. Radioprotection of tumor and normal tissues by thiophosphate compounds. Cancer 1973;32:528±535.
[62] Williams MV, Rojas A, Denekamp J. Tumor sensitization and protec- [40] Rasey JS, Krohn KA, Magee S, Nelson N, Chin L. Comparison of the tion: in¯uence of stromal injury on estimates of dose modi®cation. Int protective effects of three phosphorothioate radioprotectors in the J Radiat Oncol Biol Phys 1984;10:1545±1549.
RIF-1 tumor. Radiat Res 1986;108:167±175.
[63] Yuhas JM. Radiotherapy of experimental lung tumors in the presence [41] Rasey JS, Nelson NJ, Mahler P, et al. Radioprotection of normal andabsenceofaradioprotectivedrug,S-2-(3-aminopropylamino)ethyl- tissues against gamma rays and cyclotron neutrons with WR-2721: phosphorothioic acid (WR-2721). J Natl Cancer Inst 1973;50:69±78.
LD50 studies and 35S-WR-2721 biodistribution. Radiat Res 1984; [64] Yuhas JM. Active versus passive absorption kinetics as the basis for selective protection of normal tissues by S-2(3-aminopropylamino)- [42] Rojas A, Denekamp J. The in¯uence of X-ray dose level on normal ethylphosphorothioic acid. Cancer Res 1980;40:1519±1524.
tissue radioprotection by WR-2721. Int J Radiat Oncol Biol Phys [65] Yuhas JM. Protective drugs in cancer therapy: optimal clinical testing and future directions. Int J Radiat Oncol Biol Phys 1982;8:513±517.
[43] Rojas A, Stewart FA, Denekamp J. Experimental radiotherapy with [66] Yuhas JM. Ef®cacy testing of WR-2721 in Great Britain everything is WR-2721 and misonidazole. Int J Radiat Oncol Biol Phys black and white at the gray lab. Int J Radiat Oncol Biol Phys [44] Rojas A, Stewart FA, Denekamp J. Interaction of misonidazole and [67] Yuhas JM, Storer JB. Differential chemoprotection of normal and WR-2721±II. Modi®cation of tumour radiosensitization. Br J Cancer malignant tissues. J Natl Cancer Inst 1969;42:331±335.
[68] Yuhas JM, Yurconic M, Kligerman MM, West G, Peterson DF.
[45] Rojas A, Stewart FA, Soranson JA, Denekamp J. Fractionated studies Combined use of radioprotective and radiosensitizing drugs in experi- with WR-2721: normal tissues and tumour. Radiother Oncol mental radiotherapy. Radiat Res 1977;70:433±443.
[69] Yuhas JM, Afzal SMF, Afzal V. Variation in normal tissue respon- [46] Savoye C, Swenberg C, Hugot S, et al. Thiol WR-1065 and disulphide siveness to WR-2721. Int J Radiat Oncol Biol Phys 1984;10: 1537± WR-33278, two metabolites of the drug ethyol (WR-2721), protect

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