Amifostine Pretreatment Research Articles

Amifostine (WR2721) for dose escalation in marrow-ablative treatment of leukaemia

The in vivo effect of the radiochemoprotectant Amifostine on the therapeutic efficacy of marrow ablative treatment with cyclophosphamide (CP) and total body irradiation (TBI) followed by bone marrow transplantation (BMT) was studied in normal rats as well as in the Brown Norway rat acute myelocytic leukaemia (BNML) model. In normal rats, when the dose of TBI was escalated and the CP dose was kept constant, pretreatment with Amifostine yielded a positive dose modification factor of 1.26. No significant improvement was found after Amifostine pretreatment when the TBI dose was kept constant and CP dose escalated. When leukaemic rats received CP as the only antileukaemia treatment, Amifostine pretreatment did not lead to a reduction in the antileukaemic efficacy of CP, although protection against treatment-related mortality was observed. In the CP only groups, 9 out of 40 animals died of treatment-related toxicity, compared with none of the 40 animals in the Amifostine pretreatment groups. When applying the maximum tolerated treatment of CP and TBI in various combinations to leukaemic rats, 25 out of 36 rats died from treatment-related toxicity, whilst pretreatment with Amifostine reduced this to 11 out of 36, ( P=0.002). Of those animals which survived the CP+TBI conditioning treatment, 10 out of 25 in the Amifostine pretreatment group were cured, versus 8/11 in the CP+TBI only control group ( P=0.146). In conclusion, incorporation of Amifostine as a radiochemoprotectant in a marrow-ablative conditioning regimen allows the use of escalated doses of chemoradiotherapy without reducing the antileukaemic efficacy.

In vivo amifostine (WR-2721) prevents chemotherapy-induced apoptosis of peripheral blood lymphocytes from cancer patients

Aim of this work was to evaluate whether in vivo amifostine (WR-2721, ethanethiol, 2-[(3-aminopropyl) amino]-,dihydrogen phosphate (ester), Ethyol) pretreatment was able to prevent the apoptosis of peripheral blood lymphocytes (PBL s) induced by cytotoxic drugs. The study included 19 patients with advanced gynaecological cancers who received neoadjuvant polychemotherapy consisting of three cycles of cysplatin, adriamycin, and cyclophosphamide. Five patients received randomly amifostine pretreatment (910 mg m 2 ). PBL s apoptosis was measured through flow-cytometry using two different methods: a) DNA fragmentation of PBL s cultured in vitro for one hour; b) measurement of early apoptotic cells through Apostain uptake by fresh PBL s. The percentage of apoptotic PBL s was increased in all patients 24 hr after the first chemotherapy cycle (27.1 ± 15.6 vs 6.3 ± 6.2, p < 0001). A similar increase was observed in the following chemotherapy cycle. Amifostine pretreatment prevented the apoptosis of PBL s induced by chemotherapeutic drugs. Amifostine also prevented the reduction of lymphocyte number determined by chemotherapy. The results demonstrate that amifostine protects peripheral lymphocytes from the apoptotic damage induced by chemotherapy. This effect may explain the mechanism by which amifostine prevents the chemotherapy-associated reduction of leukocyte number.

In vitro effect of amifostine on haematopoietic progenitors exposed to carboplatin and non-alkylating antineoplastic drugs: haematoprotection acts as a drug-specific progenitor rescue.

We evaluated the protective ability of amifostine on peripheral blood mononuclear cell (PBMC)-derived colony-forming unit (CFU) and PB CD34+ cells which were previously exposed in vitro to etoposide, carboplatin, doxorubicin and taxotere. Amifostine pretreatment protected PBMC-derived CFU from the toxic effect of etoposide, carboplatin and taxotere. A significant detrimental effect was exerted by amifostine on the growth of doxorubicin-treated PBMC-derived CFU. Liquid cultures of PB CD34+ cells reproduced faithfully the effects observed on growth of PBMC-derived CFU and confirmed amifostine chemoprotection against etoposide and carboplatin with its detrimental effect on doxorubicin-treated progenitors. Combining the data of viable cell count, cytometric estimation of apoptosis, cell cycle and viable cell replication rate, we found that amifostine protects from etoposide and carboplatin toxicity mainly through a mechanism of cell rescue. Conversely, the detrimental effect of amifostine on the growth of doxorubicin-treated PB CD34+ cells is apparently due to an increased G2/M arrest. In conclusion, amifostine protects haematopoietic progenitors from etoposide, carboplatin and taxotere. Progenitor rescue is the mechanism through which amifostine reduced etoposide and carboplatin toxicity.

Amifostine Improves the Antileukemic Therapeutic Index of Mafosfamide: Implications for Bone Marrow Purging

One of the principal challenges of cancer chemotherapy is the relative inability of most anticancer drugs to distinguish between normal and neoplastic tissues. Consequently, a broad range of toxicities are experienced by patients, especially myelosuppression. Amifostine, a phosphorylated aminothiol, increases the selectivity of specific anticancer drugs for neoplastic cells by protecting normal tissues. One potential application of this protector is during bone marrow purging to selectively remove contaminating cancer cells. This study took normal or leukemic marrow from human subjects and evaluated the ability of amifostine to selectively protect normal bone marrow progenitor cells versus leukemic progenitor cells from the cytotoxic effect of mafosfamide. The dose response of mafosfamide amifostine on leukemia colony-forming units or normal marrow progenitor cells was determined and the LD95 was calculated. Amifostine pretreatment resulted in a statistically significant protection of granulocyte-macrophage colony-forming units and erythroid blast-forming units from the toxicity of mafosfamide (P = .031). Thus, amifostine protection of normal marrow progenitor cells allows a higher LD95 concentration of mafosfamide to be used in ex vivo purging. In contrast, amifostine pretreatment increased the cytotoxicity of mafosfamide on the fresh human leukemia progenitor cells (P = .006). The dual effect of amifostine protection of normal marrow progenitor cells coupled with amifostine-induced sensitization of the leukemia cells increases the possible cell-kill of leukemic stem cells. With amifostine pretreatment, at the LD95 concentrations of mafosfamide for marrow progenitor cells, there was an estimated 6 log increase in cell-kill of the leukemia cells. This selective cell-kill offers the potential for lowering the incidence of leukemic relapse, while preserving more normal stem cells for autologous transplantation.

Amifostine improves the antileukemic therapeutic index of mafosfamide: implications for bone marrow purging

One of the principal challenges of cancer chemotherapy is the relative inability of most anticancer drugs to distinguish between normal and neoplastic tissues. Consequently, a broad range of toxicities are experienced by patients, especially myelosuppression. Amifostine, a phosphorylated aminothiol, increases the selectivity of specific anticancer drugs for neoplastic cells by protecting normal tissues. One potential application of this protector is during bone marrow purging to selectively remove contaminating cancer cells. This study took normal or leukemic marrow from human subjects and evaluated the ability of amifostine to selectively protect normal bone marrow progenitor cells versus leukemic progenitor cells from the cytotoxic effect of mafosfamide. The dose response of mafosfamide amifostine on leukemia colony-forming units or normal marrow progenitor cells was determined and the LD95 was calculated. Amifostine pretreatment resulted in a statistically significant protection of granulocyte-macrophage colony-forming units and erythroid blast-forming units from the toxicity of mafosfamide (P = .031). Thus, amifostine protection of normal marrow progenitor cells allows a higher LD95 concentration of mafosfamide to be used in ex vivo purging. In contrast, amifostine pretreatment increased the cytotoxicity of mafosfamide on the fresh human leukemia progenitor cells (P = .006). The dual effect of amifostine protection of normal marrow progenitor cells coupled with amifostine-induced sensitization of the leukemia cells increases the possible cell-kill of leukemic stem cells. With amifostine pretreatment, at the LD95 concentrations of mafosfamide for marrow progenitor cells, there was an estimated 6 log increase in cell-kill of the leukemia cells. This selective cell-kill offers the potential for lowering the incidence of leukemic relapse, while preserving more normal stem cells for autologous transplantation.

Cisplatin-associated neurotoxicity

Neurotoxicity remains the major dose-limiting toxicity of cisplatin. Peripheral sensory neuropathy, the primary type of cisplatin neurotoxicity, has been reported in 30-100% of patients with clinical symptoms typically developing after cumulative cisplatin doses of > or = 300 mg/m2. Several clinical studies have established an important dose-response, dose intensity-response and cumulative total dose-response relationship for cisplatin in the treatment of head and neck, testicular, melanoma, and ovarian cancers. In patients with these tumor types, the occurrence of moderate or severe neuropathy presents an important therapeutic dilemma. Several types of agents--including micleophilic sulfur thiols, neurotrophic factors, phosphonic acid antibiotics and free oxygen radical scavengers--have been investigated for amelioration of cisplatin-related neurotoxicity. Of these, amifostine is likely to be the first neuroprotective agent widely used to enhance the clinical effectiveness of cisplatin. Recently reported results from a multicenter phase III trial of women with advance ovarian cancer receiving combination chemotheraphy with cisplatin plus cyclophosphamide showed that amifostine pretreatment was associated with moderate but significant reductions in cisplatin-associated peripheral neuropathy, tinnitus and nephrotoxicity, while achieving equivalent pathological response rates and median survival. Preclinical data suggest that several additional agents, especially the neurotropic factors nerve growth factor, insulin-like growth factor-I and neurotrophin-3, merit further investigation. Nerve growth factor is the only agent reported to prevent, rather than partially protect, cisplatin-induced neuropathy in an experimental model.