Phase I/II trials of WR-2721 and cis-platinum

Glover, Donna J.; Glick, John H.; Weiler, Clare; Fox, Kevin R.; Turrisi, Andrew T.; Kligerman, Morton M.

doi:10.1016/0360-3016(86)90205-1

Cited by 82 publications

(19 citation statements)

References 10 publications

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“…6 Different otoprotective drugs have been tested, and most of them act as cell free anti-radical, among which we can include amifostine (WR 2721, acid S -2[3-aminopropylamine] ethylphosphorothiol), developed by Walter Red Army Institute, in the 50's, to protect the toxic effects of radiotherapy, without affecting the antitumoral potential. 7,8 Yuhas and Culo, 1980, were the first ones to show that amifostine promoted a reduction in nephrotoxicity induced by cisplatin, without affecting antitumor activity, which was later confirmed by the studies conducted by Glover et al, 1986 and1987. 7,9,10 Mollman et al, 1988, showed slight reduction in ototoxicity of cisplatin in patients previously treated with amifostine 11 .…”

Section: Introductionmentioning

confidence: 59%

“…This fact is explained by reduction of alkaline phosphatase activity in tumor cells, low tumor vascularization and tumor anaerobe metabolism that causes a with very low pH medium, which does not allow intracellular entry of WR1065 because it requires a ph between 6.6 and 8.2. 7,8 In the 80's, amifostine was approved by FDA to be used in patients that received cisplatin to prevent cisplatin nephrotoxicity 13 . However, its use is not recommended in cases of potentially curable tumors because the influence of cisplatin in the efficacy of chemotherapy is not exactly known yet 12,14 .…”

Section: Introductionmentioning

confidence: 99%

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Otoproteção da amifostina aos efeitos ototóxicos da cisplatina: estudo em cobaias albinas por emissões otoacústicas produtos de distorção e microscopia eletrônica de varredura

Hyppolito

Oliveira

Lessa

et al. 2005

Rev. Bras. Otorrinolaringol.

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A Cisplatina é uma potente droga antineoplásica, largamente utilizada para o tratamento do câncer, tanto em adultos quanto em crianças. Dentre seus efeitos colaterais, a ototoxicidade se apresenta como um dos mais importantes e leva à perda auditiva irreversível, bilateral, para as altas freqüências (4KHz -8KHz). Estudos têm tentado identificar drogas que, associadas à cisplatina, possam atuar como otoprotetores. Sabe-se que o mecanismo da ototoxicidade pela cisplatina está relacionado a alterações nos mecanismos antioxidantes das células ciliadas, principalmente as células ciliadas externas da cóclea. A amifostina tem conhecida ação antioxidante, com conhecido efeito otoprotetor aos efeitos lesivos da radioterapia. OBJETIVO: Nossa proposta foi avaliar através de emissões otoacústicas, por produtos de distorção (EOAPD) e por microscopia eletrônica de varredura (MEV), a existência de possível efeito otoprotetor da amifostina no tratamento com cisplatina. FORMA DE ESTUDO: Experimental. MATERIAL E MÉTODO: O estudo foi realizado em cobaias albinas, que foram divididas em três grupos: Grupo 1: 6 animais -12 orelhas - cisplatina 8,0 mg/Kg/dia (via intraperitoneal) por três dias; Grupo 2: 6 animais - 12 orelhas - amifostina 100 mg/Kg/ dia (via intraperitoneal) e 90 minutos após, cisplatina 8,0 mg/Kg/dia (via intraperitoneal) por três dias; Grupo 3: 03 animais - 06 orelhas - amifostina 100 mg/Kg/dia (via intraperitoneal) por três dias. RESULTADO: Encontramos EOAPD presentes e células ciliadas externas presentes, sem lesão anatômica a MEV, nos grupos 2 e 3. Concluímos que a amifostina, por sua ação antioxidante, atua como otoprotetor a ototoxicidade pela cisplatina. No entanto, seu uso não é recomendável nos casos de tumores potencialmente curáveis, por não se saber exatamente a influência da cisplatina na eficácia da quimioterapia.

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Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Otoproteção da amifostina aos efeitos ototóxicos da cisplatina: estudo em cobaias albinas por emissões otoacústicas produtos de distorção e microscopia eletrônica de varredura

Hyppolito

Oliveira

Lessa

et al. 2005

Rev. Bras. Otorrinolaringol.

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“…503 Several preclinical and clinical studies have suggested that amifostine protects normal tissue against chemotherapy-associated toxicities without decreasing antineoplastic effects. 504,505 Animal studies suggest that amifostine scavenges hydroxyl radicals and thus markedly improves cardiac function when added to doxorubicin treatment [506][507][508] ; however, amifostine is less cardioprotective than dexrazoxane, 509 perhaps because dexrazoxane prevents the formation of radicals, whereas amifostine scavenges them.…”

mentioning

confidence: 99%

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions

Lipshultz¹,

Adams²,

Colan³

et al. 2013

Circulation

503

436

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“…Protection from CISinduced damage then occurs from this metabolite's various antioxidant actions against ROS and through proton donation to damaged DNA at the sulfhydryl sites (Culy and Spencer 2001;Treskes et al 1993). WR has been effective in ameliorating CIS-induced hematotoxicity and nephrotoxicity (Glover et al 1986) and neuropathy (Mollman et al 1988). WR's success in reducing CIS-induced ototoxicity during clinical trials is mixed, however.…”

Section: Introductionmentioning

confidence: 99%

“…Our WR dose selection (18 mg/ kg) was extrapolated from human studies (Glover et al 1986(Glover et al , 1987. It is possible that our failure to ameliorate CIS's ototoxicity was due to using a dose that was too small for the hamster.…”

Section: Introductionmentioning

confidence: 99%

WR-2721 (Amifostine) Ameliorates Cisplatin-Induced Hearing Loss But Causes Neurotoxicity In Hamsters: Dose-Dependent Effects

Church

Blakley

Burgio

et al. 2004

JARO

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Chemoprotective agents reduce the toxic side effects of chemotherapy agents such as cisplatin. The conventional belief is that the chemoprotective agent WR-2721 (Amifostine), while protecting against most cisplatin-induced side effects, does not protect against cisplatin-induced ototoxicity (i.e., hearing loss). There is no knowledge, however, about the efficacy of high doses of WR-2721 (WR) in possibly protecting against cisplatin-induced ototoxicity. Thus, the dose-dependent effects of WR in possibly ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 18, 40, 80, or 400 mg/kg/injection of the rescue agent WR (n = 5 or 10/group). Other groups received either 80 mg/kg/injection WR alone (n = 5) or were untreated (n = 14). Ototoxicity was assessed by auditory brain stem responses (ABR). WR provided dose-dependent rescue from cisplatin's ototoxicity with no protection at the low dose of 18 mg/ kg, moderate protection at 40 mg/kg, and nearly complete protection at 80 and 400 mg/kg. However, WR doses of 40 mg/kg or higher caused neurotoxicity as evidenced by prolongations in the ABR's interpeak latencies. Thus, high doses of WR provided the beneficial effect of protecting against cisplatininduced ototoxicity, but had the harmful side effect of neurotoxicity. Previous failures to find chemoprotection from cisplatin-induced ototoxicity were likely due to the use of WR doses that were too small. The clinical implications of the beneficial and harmful effects of high doses of WR are discussed.

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Phase I/II trials of WR-2721 and cis-platinum

Cited by 82 publications

References 10 publications

Otoproteção da amifostina aos efeitos ototóxicos da cisplatina: estudo em cobaias albinas por emissões otoacústicas produtos de distorção e microscopia eletrônica de varredura

Otoproteção da amifostina aos efeitos ototóxicos da cisplatina: estudo em cobaias albinas por emissões otoacústicas produtos de distorção e microscopia eletrônica de varredura

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions

WR-2721 (Amifostine) Ameliorates Cisplatin-Induced Hearing Loss But Causes Neurotoxicity In Hamsters: Dose-Dependent Effects

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