Disturbance of purine nucleotide metabolism: a possible early key event in development of intestinal damage induced by chemotherapy.

Protective strategies to minimize the hematological toxicity in connection with bone marrow transplantation (BMT) have been successful, but toxicity to the gastrointestinal tract prevents further dose escalation and therefore limits the application of the treatment. As it is known that chemotherapy leads to disruption of the intestinal barrier and morphological changes of mitochondria in enterocytes, this study was conducted in order to investigate intestinal energy metabolism and permeability after intensive cytotoxic therapy in rats. Intestinal damage was produced by intraperitoneal administration of the cytostatic etoposide. Intestinal permeability was assessed by a [51Cr]EDTA absorption test and intestinal purine nucleotide content by a high-performance liquid chromatography (HPLC) technique. Four hours after the administration of etoposide, and the next 48 hr, there was a significant increase in the intestinal permeability (P < 0.05) and a significant reduction of the purine nucleotide content in the intestinal epithelial cells (P < 0.01) as compared to control animals. This early disturbance in enterocyte energy metabolism may be a key event in the development of the intestinal damage, induced by chemotherapy, and an explanation for the early disruption of the intestinal barrier demonstrable before morphological changes are evident.

Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease: the Swedish National Health Care Programme experience.

BACKGROUND: Despite improved treatment results achieved in Hodgkin's disease (HD), only about 70% of patients with advanced stages are cured. The primary aim of this study was to evaluate the outcome of advanced stages (IIB-IVB) of HD in younger patients in an unselected population-based group of patients. The patients were recommended individualized treatment with respect to number of chemotherapy (CT) courses and post-CT radiotherapy (RT) based on pretreatment characteristics and tumour response. Secondly, we investigated if variables of prognostic importance could be detected. PATIENTS AND METHODS: Between 1985-92, 307 patients between 17-59 yr of age (median 36) were diagnosed with HD in stages IIB-IVB in 5/6 health care regions in Sweden. Median follow-up time was 7.8 yr (1.3-13). Retrospectively, laboratory parameters were collected. RESULTS: In total, 267 (87%) patients had a complete response (CR). The overall and disease-free 10-yr survivals in the whole cohort were 76% and 67%, respectively. There was no difference in survival between the groups of patients who received 6 or 8 cycles of CT. Survival was not higher for patients in CR after CT when RT was added. For those in PR after CT, additional RT raised the frequencies of CR. A selected group of pathologically staged patients was successfully treated with a short course (2 cycles) of CT + RT. In univariate analyses survival was affected by age, stage IVB, bone-marrow involvement, B-symptoms, S-LDH, S-Alb and reaching CR or not after 2, 4 and 6 cycles of CT. In a multivariate analysis, age and reaching CR after 6 cycles of CT remained statistically significant. CONCLUSIONS: The lack of difference in survival between the groups of patients who received 6 versus 8 cycles of CT indicates a successful selection of patients for the shorter treatment. Reaching a rapid CR significantly affected outcome. Whether some patients need less CT than the generally recommended 8 courses can properly only be evaluated in a randomised study. Additional RT may play a role in successful outcome, particularly if residual tumours are present, but its precise role can also only be defined in prospectively randomised studies. Reaching CR after CT was the most important variable affecting survival besides age.

Gut mucosa barrier preservation by orally administered IgA-IgG to patients undergoing bone marrow transplantation: a randomised pilot study.

Intensive cytotoxic therapy with bone-marrow transplantation (BMT) allows a potential cure for haematological malignancies. Protective strategies to minimise haematological toxicities have been successful and currently toxicity to the gastro-intestinal tract is the major cause of treatment-related morbidity and the dose-limiting factor that prevents further dose escalation. In a randomised, placebo-controlled trial we investigated whether an oral immunoglobulin preparation (IgA-IgG) can diminish intestinal toxicity with autologous BMT. IgA-IgG (n = 6) and placebo (n = 7) were orally administered from 1 day prior to the start until 1 week after the termination of the cytotoxic treatment (a total of 14 days). Intestinal toxicity was assessed by a 51Cr-EDTA absorption test for intestinal permeability and by the clinical criteria laid down by the WHO for the period before the start of the cytotoxic treatment, 1 day prior to stem-cell infusion and 4, 7, 10 and 14 days after stem-cell infusion. In the placebo group there was a significant increase in intestinal permeability on day 4 (P < 0.005) and on day 7 (P < 0.05) after stem-cell infusion, compared with the baseline, which was not seen for IgA-IgG. In addition, patients receiving IgA-IgG had significantly less intestinal permeability on day 4 (P < 0.05) and on day 7 (P < 0.05), compared with the placebo group. No significant, positive effect as regards clinical toxicity was observed. Oral administration of IgA-IgG to patients undergoing intensive cytotoxic therapy prior to BMT seems to have a protective effect on the gut mucosa barrier which is normally disrupted by this therapy.

Ascorbate preserves gastric mucosal metabolism and microcirculation after hemorrhagic shock and retransfusion in rats.

The gastric mucosal microcirculation and purine nucleotide metabolism were studied in rats after hemorrhagic shock and retransfusion. The mucosal surface density of perfused vessels (SDPV) and the mucosal levels of ATP, ADP, AMP, IMP, hypoxanthine and uric acid were measured following 15 min of hemorrhagic shock and 10 and 30 min after retransfusion, and the effects of pretreatment with allopurinol or ascorbate were studied. During shock there was a dephosphorylation of nucleotides and a decline in the SDPV. Retransfusion led to an additional reduction in the SDPV, but a complete restoration of preshock nucleotide levels 30 min after retransfusion. Allopurinol accelerated early rephosphorylation of nucleotides without effects upon SDPV while ascorbate completely preserved the mucosal level of energy-rich nucleotides 15 min after hemorrhagic shock and increased SDPV during early reperfusion. The results showed that there was a renewal of energy stores in gastric mucosa after hemorrhagic shock and retransfusion although parts of the vascular bed were not reperfused. The mucosal energy depletion after 15 min of hemorrhagic shock and part of the mucosal vessel injury after retransfusion were prevented by pretreatment with ascorbate.

Gastric mucosal microcirculation and purine nucleotide metabolism after retransfusion of rats in hemorrhagic shock.

Gastric mucosal microcirculation and purine nucleotide metabolism were studied after hemorrhagic shock and retransfusion in rats. The number of perfused microvessels and the concentration of adenosine triphosphate, adenosine monophosphate, inosine monophosphate, inosine, hypoxanthine, xanthine, and uric acid were investigated in mucosal biopsy specimens after 15 or 45 min of hemorrhagic shock and after 15 min of shock followed by 30 min of retransfusion. During shock a dephosphorylation of nucleotides and a decrease in the number of perfused microvessels occurred, the more the longer the duration of the shock period. Retransfusion led to an additional reduction in the number of perfused microvessels, but there was a partial restoration of high-energy phosphate metabolites in those areas of the mucosa which maintained a blood flow. The results indicate that there is a renewal of energy stores in gastric mucosa after hemorrhagic shock and reperfusion, although parts of the vascular bed are not reperfused.