Evaluation of uroprotective efficacy of amifostine against cyclophosphamide induced hemorrhagic cystitis.
The role of amifostine in the prevention of cyclophosphamide-induced hemorrhagic cystitis (HC) was evaluated in the rat model. Urinary bladders from control rats that received no drugs (group I) were compared with those from rats receiving cyclophosphamide alone at a dose of 150 mg/kg (group II), and two other groups receiving amifostine at 100 mg/kg (group III) and 200 mg/kg (group IV), 15 min prior to cyclophosphamide. Bladders were assessed macroscopically and histologically at 24 h and after 7 days. All the animals that received cyclophosphamide alone developed severe HC. On the basis of the scores of macroscopic and histologic changes, animals that received amifostine showed excellent uroprotection. Only 2/6 rats in group III and 1/6 rats in group IV developed mild HC at 24 h. None of the rats in either of these groups showed any evidence of HC at 7 days. It is concluded that amifostine protects the urothelium against cyclophosphamide-induced HC. (+info)
The activation of ribonucleotide reductase in animal organs as the cellular response against the treatment with DNA-damaging factors and the influence of radioprotectors on this effect.
Cellular requirements for deoxyribonucleotide (dNTP) pools during DNA synthesis are related to ensuring of the accuracy of DNA copying during replication and repair. This paper covers some problems on the reactions of dNTP synthesis system in organs of animals against the treatment with DNA-damaging agents. Ribonucleoside diphosphate reductase (NDPR) is the key enzyme for the synthesis of dNTP, since it catalyses the reductive conversion of ribonucleotides to deoxyribonucleotides. The results obtained show that the rapid and transient increase in NDPR activity in animal organs occurs as cellular response against the treatment with DNA-damaging agents (SOS-type activation). We have also found the intensive radioprotector-stimulated activation of deoxyribonucleotide synthesis as well as DNA and protein synthesis in mice organs within 3 days after the administration of two radioprotectors, indralin and indometaphen, that provide the high animal survival. Our studies suggest that these effects are the most important steps in the protective mechanism of the radioprotectors and are responsible for the high animal survival. (+info)
Protective effects of 5,6,7,8-tetrahydroneopterin against X-ray radiation injury in mice.
The protective effects of 5,6,7,8-tetrahydroneopterin (NH4) against radiation injury in mice were studied. (C57BL/6xA/J)F1 (B6A) mice received a single whole-body irradiation dose of 200, 400, 700 or 800 cGy of X-rays. NH4 (30 mg/kg body weight) or phosphate-buffered saline (PBS) was injected intraperitoneally into irradiated mice 10 min before and after the irradiation and again after 6 h. All mice which received the 800 cGy radiation+PBS died between 8 and 11 days after the treatment. In contrast, those which also received NH4 demonstrated a significantly prolonged survival time and 40% lived more than 5 months. Total numbers of thymocytes and spleen cells on day 5 post-irradiation were dramatically reduced in line with the radiation dose. The survival was significantly enhanced by NH4 in treated mice. The proliferation of spleen cells in mice stimulated by concanavalin A (Con A) or lipopolysaccharide (LPS) was also greater in NH4 treated mice. The immune response of survivors 5 months after 800 cGy+NH4 treatments, against Con A, LPS, allogenic mouse, and sheep red blood cells had essentially recovered to the levels of normal mice. These results indicate that NH4 had an important role in modifying radiation injury. (+info)
The sulfhydryl containing compounds WR-2721 and glutathione as radio- and chemoprotective agents. A review, indications for use and prospects.
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. (+info)
Effects of radiotherapy and estramustine on the microvasculature in malignant glioma.
Tumour angiogenesis is essential for progression of solid tumours and constitutes an interesting target for therapy. However, impaired tumour blood supply may also be an important obstacle for treatment by radiotherapy and chemotherapy. Estramustine has been shown to increase tumour blood flow and potentiate the effect of radiotherapy in experimental glioma. This study investigated the effects of fractionated radiotherapy and estramustine on angiogenesis in malignant glioma. The intracerebral BT4C rat glioma model was used and the animals were given whole brain radiotherapy 4 Gy x 5 days alone or in combination with estramustine 20 mg kg(-1) i.p. daily. Tumour microvascular density (MVD) was assessed by manual and computerized morphometrical analysis. Expression of vascular endothelial growth factor (VEGF) was studied by in situ hybridization. Radiotherapy decreased MVD to 157 vessels per mm2 compared to 217 vessels per mm2 in controls. Estramustine counteracted this anti-angiogenic effect and potentiated the anti-tumoural effect of radiotherapy. In addition, vessel size increased after estramustine treatment. Five days after completion of radiotherapy the expression of VEGF was increased in the centre of the tumours. In conclusion, fractionated radiotherapy decreases microvascular density in experimental malignant glioma. This effect was abolished by estramustine. The anti-vascular effect of irradiation is important to recognize when combining radiotherapy with cytotoxic drugs. (+info)
Randomized study of a short course of weekly cisplatin with or without amifostine in advanced head and neck cancer. EORTC Head and Neck Cooperative Group.
BACKGROUND: Cisplatin is one of the most active cytotoxic agents available for the treatment of patients with head and neck cancer. In a previous phase II study with weekly administration of cisplatin, a response rate of 51% was achieved. However, only in a minority of the patients the planned high dose intensity of 80 mg/m2/week could be reached because of toxicity, mainly thrombocytopenia and ototoxicity. Amifostine is a cytoprotective drug that can diminish the toxicity of alkylating agents and platinum compounds. Therefore the effect of amifostine on toxicity and activity of weekly cisplatin was investigated in a randomized study. PATIENTS AND METHODS: Patients with locally advanced, recurrent or metastatic head and neck cancer were eligible. Patients were randomized to weekly cisplatin 70 mg/m2 for six cycles preceded by amifostine 740 mg/m2, or cisplatin only. Cisplatin was administered in hypertonic saline (3% NaCl) as a one-hour infusion; amifostine was administered as a 15-minute infusion directly before the administration of cisplatin. RESULTS: Seventy-four patients were entered in the study. The median number of cisplatin administrations was 6 (range 2-6), equal in both arms. In both treatment arms the median dose intensity of cisplatin achieved was the planned 70 mg/m2/week. In the cisplatin only arm 6 out of 206 cycles were complicated by thrombocytopenia grade 3 or 4 versus 1 of 184 cycles in the amifostine arm (P = 0.035). Hypomagnesaemia grade 2 + 3 was significantly less observed in the amifostine arm (P = 0.04). Neurotoxicity analyzed by serial vibration perception thresholds (VPT) showed a diminished incidence of subclinical neurotoxicity in the amifostine arm (P = 0.03). No protective effect on renal and ototoxicity could be shown. Hypotension was the main side effect of amifostine but only of relevance in one patient. The antitumor activity of cisplatin was preserved as 63% of the evaluable patients in the amifostine arm responded compared to 50% of the evaluable patients in the cisplatin alone arm. CONCLUSION: Our study indicated that in combination with weekly administered cisplatin amifostine reduced the risk of thrombocytopenia, hypomagnesemia as well as subclinical neurotoxicity, but did not result in a higher dose intensity of cisplatin. Addition of amifostine did not compromise the antitumor effect of cisplatin. (+info)
Short-term, serum-free, static culture of cord blood-derived CD34+ cells: effects of FLT3-L and MIP-1alpha on in vitro expansion of hematopoietic progenitor cells.
BACKGROUND AND OBJECTIVE: The use of ex vivo expanded cells has been suggested as a possible means to accelerate the speed of engraftment in cord blood (CB) transplantation. The aim of this study was to fix the optimal condition for the generation of committed progenitors without affecting the stem cell compartment. DESIGN AND METHODS: Analysis of the effects of FLT3-L and MIP-1alpha when combined with SCF, IL-3 and IL-6, in short-term (6 days), serum-free expansion cultures of CB-selected CD34+ cells. RESULTS: An important expansion was obtained that ranged between 8-15 times for CFU-GM, 21-51 times for the BFU-E/CFU-Mix population and 11 to 30 times for CD34+ cells assessed by flow cytometry. From the combinations tested, those in which FLT3-L was present had a significant increase in the expansion of committed progenitors, while the presence of MIP-1alpha had a detrimental effect on the generation of more differentiated cells. However, stem cell candidates assessed by week 5 CAFC assay could be maintained in culture when both MIP-1a and FLT3-L were present (up to 91% recovery). This culture system was also able to expand megakaryocytic precursors as determined by the co-expression of CD34 and CD61 antigens (45-70 times), in spite of the use of cytokines non-specific for the megakaryocytic lineage. INTERPRETATION AND CONCLUSIONS: The results obtained point to the combination of SCF, IL-3, IL-6, FLT3-L and MIP-1alpha as the best suited for a pre-clinical short-term serum-free static ex vivo expansion protocol of CB CD34+ cells, since it can generate large numbers of committed progenitor cells as well as maintaining week 5 CAFC. (+info)
Radioprotective effects of sodium tungstate on hematopoietic injury by exposure to 60Co gamma-rays in Wistar rats.
Radioprotective effects of sodium tungstate (ST) on 60Co gamma-ray induced decrease in hematocrit value and in survival rate in Wistar strain male rats were examined. A long-term administration of ST (less than 150 mg/kg body weight/day) for 60-300 days had no significant effects on body and organs weights and survival days. The LD50/60 in 20 weeks old rats was 220 mg/kg body weight/day. Daily administration of 38, 75 or 150 mg from 7 days before and after irradiation to 60 days significantly mitigated the decrease in hematocrit values, especially at 23 days after irradiation (P < 0.05). The highest mitigation rate of the decrease in hematocrit value was observed in rats administered at a dose of 38 mg ST/day. Simultaneously, a dose of 38 mg ST/day inhibited lethal effect of 60Co gamma-rays significantly. The dose-reduction factor for survival of 38 mg ST administered rats was 1.14. (+info)