Testicular and epididymal spermatozoa are used routinely for intracytoplasmic sperm injection (ICSI) to treat men with obstructive azoospermia. Little is known of the effects of obstruction and stasis on the DNA of these spermatozoa, particularly in the epididymis where spermatozoa have been retained for long periods. Surgical epididymal aspiration for ICSI could provide spermatozoa that are senescent or dying. Using the Comet assay, the percentage of undamaged DNA of testicular spermatozoa from 20 men with obstructive azoospermia was significantly better (83.0 +/- 1. 2%) than from proximal epididymal spermatozoa (75.4 +/- 2.3%; P < 0. 05). There was no difference between the percentage of undamaged DNA of testicular spermatozoa from 39 men with obstructive azoospermia (84.0 +/- 0.9) or from 10 fertile men at vasectomy (86.8 +/- 1.8) or from ejaculated spermatozoa from five of the controls (78.9 +/- 3.9; P > 0.05). In nine subjects, a second biopsy was carried out 6 months later. There was no significant difference in undamaged DNA on these two occasions (83.5 +/- 5.6 and 84.1 +/- 4.2; P > 0.05). This confirms the reproducibility of the Comet assay for non-ejaculated spermatozoa. Our data suggest that testicular sperm DNA appears to be significantly less damaged than epididymal sperm DNA, and so testicular spermatozoa should be used in preference for ICSI to treat men with obstructive azoospermia.
SummaryThe direct detection and monitoring of anti-cancer drugs in vivo by magnetic resonance spectroscopy (MRS) may lead to improved anti-cancer strategies. 31P-MRS has been used to detect and quantify ifosfamide (IF) in vivo in GH3 prolactinomas and N-methyl-Nnitrosourea (MNU)-induced mammary tumours in rats. The average concentration of IF in the GH3 prolactinoma over the first 2 h following a dose of 250 mg kg-' i.v. was calculated to be 0.42 ,umol g-1 wet weight, with a half-life of elimination (t,,2) of 2-4 h. Carbogen (95% oxygen/5% carbon dioxide) breathing increased the amount of IF taken up by the GH3 prolactinoma by 50% (P<0.01) to 0.68 ,umol g-1 wet weight, although t,,2 elimination rates were unchanged. IF was also detected in the liver in vivo, with a t,,c of about 1 h. Carbogen breathing did not affect the maximum peak area (Cmax) or the t,,2 in the liver. Most importantly, the carbogen-induced increase in IF uptake by the tumour caused significant growth delay at all time points in the GH3 tumour growth between day 5 and day 12 (P < 0.01) compared with IF alone. These findings show that carbogen breathing has potential for increasing the efficacy of anti-cancer drugs. Isolated GH3 cells were sensitive to the parent drug (IF) in vitro (C~50 = 1.3 ± 0.2 mM) suggesting that the GH3 cells may be either expressing P450 enzymes or are sensitive to the parent drug per se.
Summary The effects of different doses of hydralazine and prostacyclin on the 31P magnetic resonance spectra of the LBDS, fibrosarcoma were investigated and related to their effects on mean arterial blood pressure (MABP) and heart rate. The effect of reducing MABP by bleeding the animals, via the tail artery, was also investigated. Tumour spectral changes following high dose drug treatment (an (Hahn, 1974;Overgaard & Bichel, 1977;Overgaard & Nielsen, 1980). Hydralazine has also been shown to potentiate the cytotoxicity in solid rodent tumours in vivo of the bioreductive drugs RSU-1069(Chaplin & Acker, 1987 and SR4233 (Brown, 1987). These drugs are cytotoxic to hypoxic cells and their potentiation by hydralazine is presumably brought about by induced hypoxia secondary to a decrease in tumour blood flow.Selective reduction of tumour blood flow also has potential in more conventional chemotherapy. Stratford et al. (1987) showed that a carefully timed administration of hydralazine could increase the cytotoxic action of melphalan in transplanted rodent tumours whilst normal tissue toxicity remained unaffected. This could be explained by a hydralazine-induced selective reduction in tumour blood flow leading to entrapment of melphalan in the tumour tissue.Hydralazine is used clinically to control hypertension. Its plasma half-life in man is less than 60 min (Shepherd et al., 1980), but its half-life in vascular smooth muscle may be as high as 30 h (Gross, 1977) which is a possible disadvantage for application in tumour therapy. Horsman et al. (1989) have shown that, in mice, the mean arterial blood pressure, which falls on administration of hydralazine, has not returned to normal 8 h after injection. Tumour blood flow was not measured directly but there was also some indication that it too had not returned to pre-drug levels by 8 h. Any longterm reduction in the tumour blood supply would be a disadvantage for radiotherapy. Therefore, in the present study, the effect of hydralazine on cardiovascular parameters and tumour energy metabolism was compared with that of prostacyclin, an endogenous vasodilator formed from arachidonic acid (Moncada et al., 1976). This compound is rapidly hydrolysed in whole blood and plasma with a half-life of around 6 min (Orchard & Robinson, 1981). In man, the onset and offset of the cardiovascular actions of prostacyclin are rapid, less than 5 min, which means that its effects can be easily reversed (O'Grady et al., 1980;Lewis & Dollery, 1983
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