Haematologica
-
Amifostine is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[(3-aminopropyl)amino]dihydrogen phosphate. It is a pro-drug of free thiol that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs, and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project. Following declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. In fact, pretreatment with amifostine was well tolerated and reduced the cumulative hematologic, renal and neurological toxicity associated with cisplatin, cyclophosphamide and vinblastine therapy of advanced and metastatic solid tumors. The objective of this review is to focus the importance of amifostine as a myeloprotective and cytoprotective drug during treatment with chemotherapeutics, presenting the most recent results, and to discuss the application of amifostine in the therapy of myelodysplastic syndromes. ⋯ Amifostine, formerly known as WR-2721, is an organic thiophosphate that was developed to protect normal tissues selectively against the toxicities of chemotherapy and radiation. Amifostine is a pro-drug that is dephosphorylated at the tissue site to its active metabolite by alkaline phosphatase. Differences in the alkaline phosphatase concentrations of normal versus tumor tissues can result in greater conversion of amifostine in normal tissues. Once inside the cell the free thiol provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapies. Preclinical animal studies demonstrated that the administration of amifostine protected against a variety of chemotherapy-related toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity, and the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related chemotherapeutic agents. Amifostine was shown to protect a variety of animal species from lethal doses of radiation. Studies in tumor-bearing animals demonstrated that the administration of amifostine results in cytoprotection without loss of antitumor activity. Multiple phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine resulted to be 740-910 mg/m(2) in a single dose regimen, and 340 mg/m(2) in a multiple dose regimen. Amifostine afforded not only hematologic protection, but also other organ protection from cytotoxic agents such as nephrotoxicity, mucositis and peripheral neuropathy from cisplatin. Many studies have been performed to investigate cytoprotective efficacy of amifostine. In brief, amifostine gives hematologic protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin, and salivary gland from radiotherapy. In phase I/II studies these properties have been confirmed, together with a generally good tolerability of the drug, hypotension being the most common side effect. It has been observed that amifostine possibly enhances the anti-tumor effect of carboplatin, nitrogen mustard, melphalan, and cisplatin combined with 5-FU or vinblastine. For all these characteristics, amifostine is at present broadly used as supportive treatment during chemotherapy, in lymphomas and solid tumors, and its spec
-
High-dose chemotherapy and autologous bone marrow transplantation (ABMT) has become the standard approach for most patients with relapsed or refractory Hodgkin's disease. Disease status at transplant has been correlated with outcome following ABMT. In light of this, we employ mini-BEAM (BCNU, etoposide, cytarabine and melphalan) salvage therapy in order to achieve a state of minimal residual disease prior to transplantation. ⋯ Mini-BEAM is an effective salvage regimen with moderate toxicity that may be useful for cytoreduction prior to stem cell procedures.
-
Randomized Controlled Trial Comparative Study Clinical Trial
Prospective, randomized trial of sequential interleukin-3 and granulocyte- or granulocyte-macrophage colony-stimulating factor after standard-dose chemotherapy in cancer patients.
Several in vitro and animal studies have shown that IL-3 primes hematopoietic stem cells to become more sensitive to later acting growth factors. We wanted to compare the toxicity and the synergistic stimulatory effect of interleukin-3 (IL-3) followed by granulocyte colony-stimulating factor (G-CFS) or granulocyte-macrophage colony-stimulating factor (GM-CSF) on white blood cell (WBC) and platelet counts, after standard-dose chemotherapy (CT) in patients with solid tumors. ⋯ The nadir of WBC in the cycles supported with the combination of IL-3 and G-CSF was significantly higher than that observed in the CT cycles not supported by growth factors (p < 0. 005). Furthermore, severe leukopenia was abrogated in all the cycles supported with IL-3+G-CSF, while in the cycles without cytokines, this event was registered in 62.5% of the cases (p < 0.0005). Finally, the recovery of WBC was achieved a mean of 4 days earlier in the cycles supported with IL-3+G-CSF. As for thrombocytoprotection, no significant differences were evidenced, but severe thrombocytopenia was abrogated in all the cycles supported by IL-3+G-CSF (p < 0.05). Furthermore, platelet recovery after CT was achieved on average 3.5 days earlier in the IL-3+G-CSF group than in the previous cycles. The nadir of WBC count in the cycles supported by the combination of IL-3 and GM-CSF was significantly higher than that observed in the CT cycles not supported by growth factors (p < 0.005). Furthermore, severe leukopenia was abrogated in 40% of the cycles supported by IL-3+GM-CSF, while in the cycles without cytokines, this event was registered in 80% of the cases (p < 0.005). Finally, the recovery of WBC was achieved a mean of 3.5 days earlier in the cycles supported by IL-3+GM-CSF. As far as thrombocytoprotection is concerned, there were no significant differences in the nadir between the cycles supported by the association IL-3+GM-CSF and the cycles not supported by cytokines. However, severe thrombocytopenia was registered in 20% of the cycles not supported by growth factors but in only 10% of the cycles supported by IL-3+GM-CSF (p < 0.05). Furthermore, platelet recovery after CT was achieved on average 3 days earlier in the IL-3+GM-CSF group. The combination of IL-3 and G-CSF would appear to be more effective than the combination of IL-3 and GM-CSF in the control of both severe thrombocytopenia and leukopenia. Indeed, severe leukopenia was abrogated in all the cycles in arm A, but only in 40% of the cycles in arm B (p < 0.0005). Furthermore, considering a platelet count below 49