Randomized trial of carboplatin plus amifostine versus carboplatin alone in patients with advanced solid tumors

Budd, G. Thomas; Ganapathi, Ram; Adelstein, David J.; Pelley, Robert J.; Olencki, D O Thomas; Petrus, John; McLain, B S Denise; Zhang, Jianliang; Capizzi, Robert L.; Bukowski, Ronald M.

doi:10.1002/(sici)1097-0142(19970915)80:6<1134::aid-cncr17>3.0.co;2-9

Cited by 46 publications

(8 citation statements)

References 9 publications

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“…The recommended dose of amifostine is 740-910 mg/m 2 in humans for myelo-and nephroprotection. Pretreatment with amifostine (50-300 mg/kg) had a significant protective effect against various adriamycin-induced toxicities in rats (Holford 1996;Budd et al 1997;Jahnukainen et al 2001;Barutca et al 2004). It has a dose-related protective effect against cardiotoxicity (Dorr 1996;Dobric et al 1998;Nazeyrollas et al 1999;Bolaman et al 2001).…”

Section: Discussionmentioning

confidence: 99%

The Protective Effects of Amifostine on Adriamycin-Induced Acute Cardiotoxicity in Rats

Bolaman

Çiçek

Kadıköylü

et al. 2005

Tohoku J. Exp. Med.

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Free oxygen radicals and lipid peroxidation are responsible for adriamycin-induced cardiotoxicity. Amifostine is a scavenger of free radicals and may function as a selective cytoprotective agent. The aim of this study was to investigate the effects of amifostine on adriamycin-induced lipid peroxidation and the levels of protective enzymes in the heart. Male Wistar rats were randomly allocated to three groups: pretreated, untreated, and control (n = 10 in each group). Rats were pretreated with an intraperitoneal injection of amifostine (200 mg/kg) 30 min before the injection of adriamycin. The pretreated rats were given an intraperitoneal injection of adriamycin (10 mg/kg) and were sacrificed after 72 h. Likewise, rats received intraperitoneal injection of adriamycin (untreated) or saline (control). The hearts were removed for the analyses of malondialdehyde (MDA), reduced glutathione (GSH) and catalase. MDA levels were increased ( p < 0.005) in the heart tissues of untreated rats compared to control, while GSH and catalase levels were decreased ( p < 0.05 and p < 0.001, respectively) in untreated animals. In amifostine-preatreated group, MDA levels were lower ( p < 0.01), and GSH and catalase levels were higher ( p < 0.05 for both) than the untreated group. GSH levels were even higher in the amifostine-pretreated group compared to control ( p < 0.01), although catalase levels were significantly lower in the pretreated group ( p < 0.05). These results indicate that amifostine decreases adriamycin-induced lipid peroxidation and increases the levels of the protective enzymes in the heart tissue. Therefore, amifostine may ameliorate the adriamycin-induced acute cardiotoxicity.

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Section: Discussionmentioning

confidence: 99%

The Protective Effects of Amifostine on Adriamycin-Induced Acute Cardiotoxicity in Rats

Bolaman

Çiçek

Kadıköylü

et al. 2005

Tohoku J. Exp. Med.

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“…Furthermore, the duration of TPN and narcotic support in the control group was brief (Table 5). It may be that reductions in supportive care may only be demonstrable when amifostine is used in combination with regimens associated with more prolonged and/or severe gastrointestinal toxicity, for example, melphalan 220 mg/m 2 or multi-agent high-dose chemotherapeutic regimens such as HD-VIC 9,20 Work undertaken combining amifostine pre-and posttreatment with carboplatin in patients with various cancers has demonstrated a reduction in dose-limiting thrombocytopenia despite enhanced drug delivery 31,32 Likewise, the severity and duration of neutropenia secondary to cyclophosphamide can be ameliorated by amifostine. 17 These effects would appear to be due principally to the ability of amifostine to protect haemopoietic progenitors from a range of chemotherapeutic agents, as shown by in vitro clonogenic assays 17,33,34 and further supported by engraftment data from a randomised trial of in vitro amifostine in the context of 4-HC purged bone marrow prior to transplantation.…”

Section: Discussionmentioning

confidence: 99%

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation

Spencer

Horvath

Gibson

et al. 2005

Bone Marrow Transplant

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Summary:In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n ¼ 43) or not receive (n ¼ 47) amifostine 910 mg/m 2 prior to melphalan 200 mg/m 2 . Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P ¼ 0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P ¼ 0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P ¼ 0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to highdose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis. Bone Marrow Transplantation (2005) 35, 971-977.

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“…This remnant can form complexes with cisplatin. In carboplatin and paclitaxel in vitro and in vivo no adverse effect on tumour response is found when WR-2721 is given simultaneously (Taylor et al, 1997;Budd et al, 1996). Based on these results, WR-2721 drug complex formation might be not so important for these two drugs.…”

Section: Wr-2721 Characteristicsmentioning

confidence: 84%

The sulfhydryl containing compounds WR-2721 and glutathione as radio- and chemoprotective agents. A review, indications for use and prospects

1999

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Radio- and chemotherapy for the treatment of malignancies are often associated with significant toxicity. One approach to reduce the toxicity is the concomitant treatment with chemoprotective agents. This article reviews two sulfhydryl compounds, namely the agent WR-2721 (amifostine), a compound recently registered for use in human in many countries, and the natural occurring compound glutathione (GSH). GSH is not registered as a chemoprotective agent. WR-2721 is an aminothiol prodrug and has to be converted to the active compound WR-1065 by membrane-bound alkaline phosphatase. WR-1065 and GSH both act as naturally occurring thiols. No protective effect on the tumour has been found when these compounds are administered intravenously. There is even in vitro evidence for an increased anti-tumour effect with mafosfamide after pretreatment with WR-2721, and in vivo after treatment with carboplatin and paclitaxel. Randomized clinical studies have shown that WR-2721 and GSH decrease cisplatin-induced nephrotoxicity and that WR-2721 reduces radiation radiotherapy-induced toxicity. Side-effects associated with WR-2721 are nausea, vomiting and hypotension, GSH has no side-effects. An exact role of WR-2721 and GSH as chemoprotectors is not yet completely clear. Future studies should examine the protective effect of these drugs on mucositis, cardiac toxicity, neuro- and ototoxicity, the development of secondary neoplasms and their effect on quality of life. © 1999 Cancer Research Campaign

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Randomized trial of carboplatin plus amifostine versus carboplatin alone in patients with advanced solid tumors

Cited by 46 publications

References 9 publications

The Protective Effects of Amifostine on Adriamycin-Induced Acute Cardiotoxicity in Rats

The Protective Effects of Amifostine on Adriamycin-Induced Acute Cardiotoxicity in Rats

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation

The sulfhydryl containing compounds WR-2721 and glutathione as radio- and chemoprotective agents. A review, indications for use and prospects

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