Amifostine impairs p53-mediated apoptosis of human myeloid leukemia cells.
(49/192)
Amifostine is used as a cytoprotective agent in cancer treatments. Amifostine protects from apoptosis in some models and has been used as hematopoiesis stimulator in myeloid malignancies. As the apoptosis induced by many antitumoral agents is mediated by p53, we studied the effect of amifostine on p53-mediated apoptosis. We used human myeloid leukemia K562 and NB4 cells expressing the temperature-conditional p53-Val(135) mutant. Both cell lines undergo apoptosis at 32 degrees C due to the presence of p53 in wild-type conformation. We found that amifostine dramatically reduced apoptosis by p53 in both cell lines, as assessed by cell morphology, annexin V binding, fraction of sub-G(1) cells, and DNA laddering. To explore the mechanism responsible for this apoptosis protection, we tested the effect of amifostine on p53 transcriptional activity. We found that amifostine reduced p53-mediated transactivation of target promoters in NB4 and K562. Macroarray analysis confirmed that several p53 target genes as p21(Waf1), mdm2, gadd45, pig8, and pig3 were down-regulated at the mRNA level by amifostine in NB4 and K562. Also, c-myc was up-regulated by amifostine in K562 in the presence of p53, consistently with the impairment of p53-mediated apoptosis exerted by c-Myc in these cells. We conclude that amifostine impairs p53-dependent apoptosis of myeloid leukemia cells by reducing the activation of apoptosis-related genes. Our results open the possibility that amifostine could reduce the effectiveness of antitumoral treatments when it is dependent on active p53. (+info)
Limited access trial using amifostine for protection against cisplatin- and three-hour paclitaxel-induced neurotoxicity: a phase II study of the Gynecologic Oncology Group.
(50/192)
PURPOSE: The purpose of this study was to determine whether amifostine (WR-2721) prevents or ameliorates clinically significant (grade 2 to 4) neurotoxicity associated with cisplatin and 3-hour paclitaxel chemotherapy. MATERIALS AND METHODS: The chemotherapy program consisted of intravenous paclitaxel 175 mg/m2 over 3 hours followed by amifostine 740 mg/m2 and cisplatin 75 mg/m2 administered over 90 minutes beginning 15 minutes after amifostine administration. At baseline, before each treatment cycle, and for 3 months after completing chemotherapy, patients were evaluated for evidence of neurotoxicity and other treatment-related adverse effects using three methods: standard clinical evaluation (National Cancer Institute common toxicity criteria [CTC] grading), a neurotoxicity questionnaire to assess symptoms and limitations imposed by peripheral neuropathy, and vibration perception threshold (VPT) testing. RESULTS: Four of 27 assessable patients developed grade 2 to 4 neurotoxicity based on clinical assessments and CTC grading. This number of neuropathic events exceeded the predetermined threshold level for a second stage of accrual and the study was closed. CONCLUSION: Amifostine's level of activity in this trial was insufficient to warrant further study in a phase III trial. Based on the receiver operating characteristic analysis, it would appear that VPT measurements are less sensitive to the development of peripheral neuropathy than the neurotoxicity questionnaire. The questionnaire, referred to as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, may be used instead of VPT measurements in future studies of chemotherapy-induced peripheral neuropathy. (+info)
Neurophysiological study of peripheral neuropathy after high-dose Paclitaxel: lack of neuroprotective effect of amifostine.
(51/192)
PURPOSE: To determine if there is a beneficial effect of amifostine in preventing or reducing the neuropathy induced by high-dose paclitaxel. METHODS: Breast cancer patients receiving high-dose infusional paclitaxel (725 mg/m(2)/24 h) in combination with doxorubicin (165 mg/m(2)/96 h) and cyclophosphamide (100 mg/kg/2 h; ACT) were studied on two autologous peripheral blood stem cell transplant protocols, one with and one without amifostine (740 mg/m(2) administered over 10 min before and 12 h after initiation of the paclitaxel infusion). Patients were evaluated before ACT and 20-40 days later with neurological examination, a composite peripheral neuropathy score, peroneal and sural nerve conduction studies, and quantitative sensory testing. RESULTS: There was no significant difference in paclitaxel maximum concentration, systemic clearance, or area under the curve determinations. Narcotic requirement as well as recovery of hematopoietic counts were also similar in subjects with or without amifostine. After ACT was administered, there was a decrease in peroneal nerve compound muscle action potential amplitude and sural nerve sensory action potential amplitude, as well as an increase in vibratory and cold detection thresholds. Clinical composite peripheral neuropathy scores were similar despite amifostine treatment; and logarithm to the base 2 ratios post/pre ACT showed no significant effect of amifostine on peroneal nerve compound muscle action potential, sural nerve sensory action potential, vibratory detection thresholds, or cold detection thresholds. All subjects had acroparesthesias and lost their ankle deep-tendon reflexes after administration of ACT. CONCLUSIONS: Single high-dose paclitaxel produces predictable clinical and neurophysiological changes so that patients receiving high-dose therapy are ideal subjects to test the effectiveness of neuroprotective agents. Amifostine was ineffective in preventing or reducing the neurotoxicity of high-dose paclitaxel. (+info)
WR-2721 (Amifostine) ameliorates cisplatin-induced hearing loss but causes neurotoxicity in hamsters: dose-dependent effects.
(52/192)
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 cisplatin-induced 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. (+info)
Amifostine protects against chemotherapy-induced neurotoxicity: an in vitro investigation.
(53/192)
BACKGROUND: Peripheral neurotoxicity is a dose-limiting side-effect of a number of effective chemotherapeutic agents. Neuroprotective agents may help to reduce neurotoxicity, thus allowing the intensification of cytostatic therapy in patients. MATERIALS AND METHODS: In this in vitro study, using the rat pheochromocytoma cell line PC-12 neurite-outgrowth assay, the potential of amifostine to protect against cisplatin-, paclitaxel- and vincristine-induced neurotoxicity was investigated Amifostine is described as selectively protecting normal tissue and not tumour tissue. The effect of amifostine on tumour cell kill was investigated using the XTT and colony forming assay. RESULTS: Paclitaxel and vincristine both caused a significant reduction in the percentage of cells expressing neurites. Co-incubation with amifostine significantly increased this percentage of neurites in paclitaxel-induced neurotoxicity, but not in vincristine-induced neurotoxicity. Post-incubation of amifostine also proved to partly reverse already existing cisplatin-induced neurotoxicity, but not paclitaxel-, or vincristine-induced neurotoxicity. Amifostine did not protect tumour cells against cisplatin- and paclitaxel-induced tumour cytotoxicity, using the XTT assay. However, a stimulation of clonogenic capacity was observed when amifostine was coincubated with cisplatin. CONCLUSION: Amifostine protects against paclitaxel-induced neurotoxicity, but not against vincristine-induced neurotoxicity in this in vitro model. Furthermore, amifostine has potential to reverse already existing cisplatin-induced neurotoxicity. The role of amifostine in the proliferative potential of tumour cells in vitro needs further investigation. (+info)
BACKGROUND: Single or multiple intraoral administrations of manganese superoxide dismutase-plasmid/liposomes (MnSOD-PL) to C3H/HeNHsd mice receiving single fraction or fractionated ionizing irradiation to the head and neck region have been shown to significantly decrease mucosal ulceration, weight loss and to improve survival. MATERIALS AND METHODS: To elucidate the mechanism of irradiation protection by MnSOD-PL and explore possible additive or synergistic protective effects with Amifostine (WR2721), mice received a single fraction of 19, 22.5, 25 or 30 Gy, or 24 fractions of 3 Gy irradiation to the oral cavity and oropharynx. Multiple parameters of irradiation-induced toxicity were quantitated in subgroups of each irradiated group of mice treated with single or multiple administrations of intraoral MnSOD-PL and/or intravenous WR2721. RESULTS: In 19 Gy single fraction irradiated mice, MnSOD-PL treatment the day before irradiation alone or in combination with intravenous WR2721 significantly decreased the irradiation induction of mucosal cell cycling as measured by 5-bromo-2-deoxyuridine (BuDR) uptake in oral cavity mucosal cells at 48 hours and decreased ulceration of the tongue at nine days after irradiation compared to control, irradiated or irradiated, WR2721-treated mice. Mice treated in single fractions of 22.5, 25 or 30 Gy showed MnSOD-PL protection against irradiation-induced oral mucosal apoptosis and xerostomia measured in decreased saliva output. In fractionated irradiated mice, twice weekly hemagglutinin (HA) epitope-tagged MnSOD uptake in oral cavity and tongue mucosal cells was not detectably altered by daily WR2721 intravenous administration. Mice treated with both radioprotective agents (MnSOD-PL and WR2721) demonstrated a significant decrease in irradiation-induced xerostomia (measured as reduced salivary gland output volume), mucosal ulceration and improved survival. CONCLUSION: Enhanced salivary gland function in WR2721-treated mice in the absence of detectable mucosal protection, coupled with relatively low uptake of HA-MnSOD in the salivary glands of intraorally-treated mice, suggests that a combination of both radioprotective agents may prove optimally effective for the prevention of the acute and late normal tissue toxicities of fractionated radiotherapy for head and neck cancer. (+info)
Conformal hypofractionated and accelerated radiotherapy with cytoprotection (HypoARC) for high risk prostatic carcinoma: rationale, technique and early experience.
(55/192)
Recent radiobiological analysis of the radiotherapy results for prostate cancer revealed that prostate carcinoma behaves as a late responding tissue, sharing an alpha/beta ratio lower than 2Gy. These findings suggest that hypofractionation may be more effective. Reduction of the overall treatment time could further increase response by abrogating the effect of rapid tumor repopulation. In the present study we report a conformal technique applied (to pelvis and prostate) for the treatment of high-risk prostate cancer, using hypofractionated and accelerated radiotherapy (3.4Gy x 15 consecutive fractions) supported with high-dose daily amifostine (1000mg subcutaneously) to protect normal tissues against early and late effects. The biological dose delivered to the prostate cancer by this HypoARC (hypofractionated accelerated radiotherapy with cytoprotection) technique is estimated to be 71.4Gy (alpha/beta= 1.5 Gy). The time-adjusted biological dose is estimated to 77-94 Gy. Amifostine tolerance was excellent. All seven patients recruited up to now have accomplished their treatment with grade 0-1 cystitis or diarrhoea (5/7 grade 0). The study is ongoing to assess efficacy and late effects of HypoARC. (+info)
Outcome of local application of amifostine (WR-1065) on epirubicin-induced oral mucositis. A phase II study.
(56/192)
BACKGROUND: Intravenous administration of amifostine reduces chemotherapy-induced toxicity. Preclinical experiments showed a reduction in radiation-induced mucositis after local application of the active metabolite of amifostine (WR-1065). This study evaluated the effect of local application of WR-1065 on chemotherapy-induced oral mucositis. PATIENTS AND METHODS: Non-small cell lung cancer patients treated with gemcitabine and epirubicin every 3 weeks for a maximum of five cycles were included. WR-1065 was administered during the second and third cycle as an oral rinse. Oral mucositis evaluation included WHO toxicity grading, a validated oral mucositis assessment scale (OMAS) and a questionnaire. RESULTS: Twenty-four patients were evaluated for at least one control and one rinse cycle. Mucositis scores, pain and feeding difficulties increased from day 1 to day 15, and were not significantly different between the control and rinse cycles. Local application of WR-1065 leads to detectable quantities of WR-1065 in epithelial mucosa cells. A negative correlation between the WR-1065 concentration and OMAS score was found. CONCLUSION: No clinical detectable influence of WR-1065 on oral mucositis was found. (+info)