The modification of melphalan toxicity in tumor bearing mice by S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR2721)

Millar, J. L.; McElwain, T. J.; Clutterbuck, R. D.; Wist, Erik

doi:10.1097/00000421-198206000-00015

Cited by 65 publications

(19 citation statements)

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“…9 Amifostine is a radioprotectant pro-drug that upon activation via dephosphorylation confers protection to normal but not malignant cells against oxygen-based radicals and electrophilic reactive drugs such as alkylator (nitrogen mustard, cyclophosphamide, melphalan) and organoplatinum anticancer drugs. [10][11][12][13][14][15][16][17] In animal models amifostine produces a significant increase in resistance to haemopoietic injury from alkylating agents and the nephrotoxicity of cisplatin, without altering antitumour activity. 10,14,18 Laboratory data suggest that the mechanism of amifostine's selective protection is related to its preferential uptake in normal vs malignant tissues.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12][13][14][15][16][17] In animal models amifostine produces a significant increase in resistance to haemopoietic injury from alkylating agents and the nephrotoxicity of cisplatin, without altering antitumour activity. 10,14,18 Laboratory data suggest that the mechanism of amifostine's selective protection is related to its preferential uptake in normal vs malignant tissues. 13,19 This is in part due to the better vascularity, higher alkaline phosphatase levels (required for dephosphorylation of the prodrug to its active metabolite -the free thiol WR-1065), and the higher pH of normal tissue.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Whether BEAM is more toxic than BEAC in this age group is as yet unknown. Experimentally, amifostine has been shown to reduce hematopoietic and mucosal toxicity of melphalan 19 and is now also undergoing clinical trials in patients receiving HDT supported by PBSCT. Higher progenitor cell numbers infused may further decrease the toxicity associated with ASCT.…”

Section: Discussionmentioning

confidence: 99%

Feasibility and toxicity of high-dose chemotherapy supported by peripheral blood stem cell transplantation in elderly patients (⩾60 years) with non-Hodgkin’s lymphoma: comparison with patients <60 years treated within the same protocol

Jantunen

Mahlamäki

Nousiainen

2000

Bone Marrow Transplant

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Summary:Limited data are available concerning feasibility and toxicity of progenitor cell mobilization and high-dose therapy (HDT) supported by peripheral blood stem cell transplantation (PBSCT) in elderly patients (у60 years) with non-Hodgkin's lymphoma (NHL). From 1995 to 1999, 17 elderly NHL patients (median age 63 years, range 60-70) entered our HDT program and were mobilized with CY (4 g/m 2 ) followed by G-CSF. Mobilization was successful in 13 patients, who then received BEAM or BEAC followed by PBSCT. The feasibility and toxicity of progenitor cell mobilization and HDT in the elderly patients were compared with experiences in 62 NHL patients Ͻ60 years (median 46 years, range 16-59), who received the same mobilization protocol and of whom 48 patients received HDT supported by PBSCT. No significant differences were observed between these groups in the success rate of progenitor cell mobilization, in the number of CD34-positive cells collected or in the number of aphereses needed. HDT appeared to be somewhat more toxic in the elderly patients: a higher peak CRP value (P = 0.08) and longer in-hospital stay (P = 0.05) were observed. No differences were found in transplant-related mortality or severe organ toxicity between these age groups except for oral mucositis grade Ͼ2, which tended to be more common in the elderly patients (P = 0.07). We conclude that progenitor cell mobilization and HDT supported by PBSCT is also feasible in selected elderly patients with NHL. Bone Marrow Transplantation (2000) 26, 737-741.

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“…WR-2721 is unable to pass through the blood-brain barrier and cannot be used as a protective agent for the brain and spinal cord (Washburn et al, 1976;Millar et al, 1982). The drug-related toxicities in humans (Kemp et al, 1996) include hypotension (57%), flushing (39%), sneezing (25%), dizziness (11%) and chills (4%).…”

Section: Wr-2721 Characteristicsmentioning

confidence: 99%

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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The modification of melphalan toxicity in tumor bearing mice by S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR2721)

Cited by 65 publications

References 0 publications

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

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

Feasibility and toxicity of high-dose chemotherapy supported by peripheral blood stem cell transplantation in elderly patients (⩾60 years) with non-Hodgkin’s lymphoma: comparison with patients <60 years treated within the same protocol

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

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