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PubMed1994

Analysis of long-term results and prognostic factors among 138 patients with advanced Hodgkin's disease treated with the alternating MOPP/ABVD chemotherapy.

BACKGROUND: A prospective study was conducted to assess (a) the long-term results and toxicity of the alternating MOPP/ABVD regimen in advanced Hodgkin's disease; (b) the prognostic value of pretreatment variables and of drug dose intensity. PATIENTS AND METHODS: A total 138 consecutive patients with advanced Hodgkin's disease entered this study; patient selection included stages IIB (33% of total), IIIB (26%), IV (25%), and stages IIA-IIIA (16%) with bulky disease and pulmonary hilum involvement. The MOPP/ABVD program was delivered in an 8-month program; adjuvant radiotherapy on sites of bulky disease was delivered in 24 patients. RESULTS: Complete remission was obtained in 106 (77%) patients; significant factors for CR in univariate analysis were stage, symptoms, histology, and bone marrow involvement. The five-year relapse-free survival (RFS) was 83%; in a multivariate analysis, histology only correlated with RFS (p = 0.04). The five-year freedom from tumor mortality and overall survival (OS) were 79% and 67%, respectively. An adverse prognostic significance for OS was observed for B symptoms and bone marrow involvement. The median percentage of relative dose intensity (RDI) was as follows: Adriamycin 86, mechlorethamine 85, vincristine 73, vinblastine 84, bleomycin 79, procarbazine 74, dacarbazine 81. No significant association was found between RDI and clinical outcome. No severe pancytopenia or life-threatening complications occurred during therapy. CONCLUSIONS: Alternating MOPP and ABVD cured more than 65% of patients with advanced HD; acute and late toxicity were acceptable. Prognostic analysis defined subgroups with a lower chance of cure which may deserve a more intensive initial therapy.

Adolescent↗
PubMed2002

Serum levels of soluble CD30 improve International Prognostic Score in predicting the outcome of advanced Hodgkin's lymphoma.

BACKGROUND: The International Prognostic Score (IPS) and circulating levels of the soluble form of CD30 molecule (sCD30) have both been associated with poor outcome in patients with advanced Hodgkin's lymphoma (HL). The aim of this study was to assess the prognostic power of the combined evaluation of sCD30 and IPS in these patients. PATIENTS AND METHODS: We included 101 patients with advanced HL, treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or MOPP (mechlorethamine, vincristine, procarbazine and prednisone)/ABVD chemotherapy with or without radiotherapy. All were tested for pre-treatment sCD30 levels. RESULTS: Six-year estimated overall survival (OS) and failure-free survival (FFS) was 89% +/- 3% and 75% +/- 4%, respectively. Thirty-three patients (33%) had IPS >2; their FFS was 60% compared with 82% in the remaining patients (P = 0.027). Serum sCD30 levels were > or =100 U/ml in 41 (41%) patients; their FFS at 6 years was 58%, compared with 87% in patients with sCD30 <100 U/ml (P = 0.003). In the 18 patients with both sCD30 > or =100 U/ml and IPS >2, FFS was significantly worse (44%) than in patients with low sCD30 and low IPS (89%) (P <0.001) or with only one of the two adverse prognostic factors (73%) (P = 0.03). CONCLUSIONS: In our study, the combination of IPS >2 and serum sCD30 levels > or =100 U/ml identifies a sizeable subgroup (18%) of advanced HL patients with very poor FFS, who might take advantage of intensified up-front treatment strategies.

Adolescent↗
PubMed2004

Comparison of MOPP versus ABVD as salvage therapy in patients who relapse after radiation therapy alone for Hodgkin's disease.

BACKGROUND: The aim of this study was to determine salvage outcome in patients with Hodgkin's disease who relapse after radiation therapy, and to compare the efficacy of mechlorethamine, Oncovin, procarbazine and prednisone (MOPP) versus Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) as salvage treatment. PATIENTS AND METHODS: One hundred patients with Hodgkin's disease (97 with stage I-II disease at presentation) who relapsed after radiation therapy alone were salvaged with either MOPP or ABVD. Freedom from second relapse (FFSR) and overall survival (OS) were determined, and prognostic factors for salvage outcome were evaluated. RESULTS: The median follow-up time since salvage therapy was 12 years. The 10-year FFSR and OS rates were 70% and 89%, respectively. Forty-one patients were salvaged with MOPP and 59 received ABVD. The type of salvage chemotherapy did not significantly influence FFSR or OS. Age >50 years at initial diagnosis was the only significant predictor for an inferior FFSR and OS on both univariate and multivariate analyses. CONCLUSIONS: The two salvage regimens of MOPP and ABVD had similar efficacy in this group of patients with predominantly early-stage disease at initial radiation therapy. The inferior salvage outcome in patients aged >50 years is a contributing factor to the overall poor prognosis of patients presenting with Hodgkin's disease at an older age.

Adult↗
PubMed1992

Expression of ribosomal phosphoprotein PO is induced by antitumor agents and increased in Mer- human tumor cell lines.

We initiated this study to determine whether three structurally related bifunctional alkylating agents could induce the expression of a presumptive human DNA repair gene. The gene chosen for this study is known to encode the ribosomal phosphoprotein PO, but ironically may also share functions related to DNA repair. We now show by Northern analysis that PO is induced by L-phenylalanine mustard, 4-hydroperoxycyclophosphamide and mechlorethamine, which are DNA-damaging agents commonly used as chemotherapeutic antitumor agents. In further support of its involvement in DNA repair is the finding of a 30- to 50-fold constitutive overexpression of the PO gene in human tumor cell lines that are Mer-, cells which lack O6-methylguanine methyltransferase activity, when compared to Mer+ cell lines. This constitutively elevated level of PO in Mer- cell lines, which are thus DNA repair defective for O6-alkyguanine lesions, was not observed for other genes tested, including the human ribosomal gene S17 whose mRNA steady-state levels were uniformly the same in both Mer- and Mer+ cells. Taking these data together, it appears that increased levels of PO are somehow linked to DNA repair, and increased expression of PO may compensate for the decreased O6-methylguanine DNA methyltransferase activity in Mer- cells. Furthermore, the PO gene has also been shown to be overexpressed in colorectal tumors and polyps and the sera of some systemic lupus erythematosus patients contain antibodies against PO. The titer of the anti-PO antibodies rises significantly during lupus psychosis.

Antineoplastic Agents↗
PubMed1987

Contribution of neutrophils and cell-mediated immunity to control of Nocardia asteroides in murine lungs.

To distinguish between the contributions of neutrophils and cell-mediated immunity to defense against Nocardia asteroides in the lung, we induced pneumonia in BALB/c mice by intranasal inoculation. We studied the course of pneumonia by histology, bronchoalveolar lavage, and quantification of colony-forming units in lungs. Mice with intact host defenses had an initial inflammatory response, consisting mostly of neutrophils, followed by a mononuclear cell infiltrate. Nocardiae were eradicated during the seven days after inoculation. Mice in which the early, predominantly neutrophil inflammatory response was prevented with mechlorethamine or antiserum to neutrophils had little inflammation, and nocardiae grew extensively. Mice in which cell-mediated immunity was impaired with cyclosporin A or cortisone acetate developed abscesses; neutrophils were abundant, but nocardiae proliferated. The occurrence of these three separate and distinct patterns suggested that both neutrophils and cell-mediated immunity are necessary for optimal control of N. asteroides infection.

Animals↗
PubMed1986

DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards.

Nitrogen mustards alkylate DNA primarily at the N7 position of guanine. Using an approach analogous to that of the Maxam-Gilbert procedure for DNA sequence analysis, we have examined the relative frequencies of alkylation for a number of nitrogen mustards at different guanine-N7 sites on a DNA fragment of known sequence. Most nitrogen mustards were found to have similar patterns of alkylation, with the sites of greatest alkylation being runs of contiguous guanines, and relatively weak alkylation at isolated guanines. Uracil mustard and quinacrine mustard, however, were found to have uniquely enhanced reaction with at least some 5'-PyGCC-3' and 5'-GT-3' sequences, respectively. In addition, quinacrine mustard showed a greater reaction at runs of contiguous guanines than did other nitrogen mustards, whereas uracil mustard showed little preference for these sequences. A comparison of the sequence-dependent variations of molecular electrostatic potential at the N7-position of guanine with the sequence dependent variations of alkylation intensity for mechlorethamine and L-phenylalanine mustard showed a good correlation in some regions of the DNA, but not others. It is concluded that electrostatic interactions may contribute strongly to the reaction rates of cationic compounds such as the reactive aziridinium species of nitrogen mustards, but that other sequence selectivities can be introduced in different nitrogen mustard derivatives.

Alkylation↗
PubMed1992

DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards is preserved in intact cells.

Nitrogen mustard alkylating agents react with isolated DNA in a sequence selective manner, and the substituent attached to the drug reactive group can impose a distinct sequence preference. It is not clear however to what extent the observed DNA sequence preferences are preserved in intact cells. The highly reiterated sequence of human alpha DNA has been used to determine the sites of guanine-N7 alkylation following treatment of cells with three nitrogen mustards, mechlorethamine, uracil mustard and quinacrine mustard, known to react in isolated DNA with distinctly different sequence preferences. Alpha DNA from drug treated cells was extracted, purified, end-labeled, and a 296 base pair, singly end-labelled, fragment isolated. Following the quantitative conversion of alkylation sites to strand breaks the fragments were separated on DNA sequencing gels. Clear differences were observed between the alkylation patterns of the three compounds, and the selectivities were qualitatively similar to those predicted and observed in the same sequence alkylated in vitro. In particular the unique preferences of uracil and quinacrine mustards for 5'-PyGC-3' and 5'-GT/GPu-3' sequences, respectively, were preserved in intact cells suggesting that the pattern of sequence dependent reactivity is not grossly affected by the nuclear milieu.

Alkylation↗
PubMed1998

Gene and human tumour cell line specific differencesin nitrogen mustard induced DNA alkylation and interstrand crosslinking frequencies.

The levels of N-alkyl purine and DNA interstrand crosslink formation, produced by the clinically used nitrogen mustard antitumour drug mechlorethamine (HN2), were quantitated at the level of specific genes in a panel of human tumour cell lines using modified Southern blotting methods. When purified genomic DNA was treated with HN2 in vitro, no significant difference in the extent of N-alkyl purine or interstrand crosslink formation in the N-ras, c-myc or CD3delta genes was observed. When the cell lines LS174T, Colo320HSR, J6 and U937 were treated with HN2, however, there was significant heterogeneity in the levels of N-alkyl purine formation in the three genes. The rank order of the extent of damage in the three genes was also different in the cell lines. The level of alkylation did not correlate with either the transcriptional activity of a gene or drug sensitivity. Crosslinks were not detectable in the N-ras or c-myc genes of LS174T, J6 or U937 cells treated with HN2, and only detectable in the amplified c-myc gene of the Colo320HSR cell line. In the related cell line Colo320DM, which has both native and translocated c-myc alleles which are both amplified and episomal, crosslinks were detected in the amplified native and rearranged c-myc alleles, and also in the N-ras gene which is also amplified in this cell line. For bifunctional alkylating agents such as HN2, therefore, heterogeneity of DNA damage can occur between different genes in human cells and can also vary for different lesions produced by the same agent. In addition, this heterogeneity can differ between human tumour cell lines.

Alkylation↗
PubMed1991

Two cycles of MOPP and radiotherapy: effective treatment for stage IIIA and IIIB Hodgkin's disease.

Two cycles of MOPP (mechlorethamine, vincristine (Oncovin), procarbazine, prednisone) and radiotherapy were used to treat 197 patients with stage III Hodgkin's disease. Prior to 1980, radiotherapy was delivered to the mantle, abdomen and pelvis; thereafter, pelvic irradiation was deleted for patients with stage III1 disease. Complete remission rates for IIIA and IIIB presentations were 91% and 89%. The 10-year freedom from tumor mortality (FTM) rate for all patients was 81%; for IIIA, it was 87% and for IIIB, it was 72%. Results were not significantly affected by gender, age, pathology, or deletion of pelvic radiotherapy. However, a subgroup of 28 patients with a tumor burden that included pelvic disease who also had B symptoms was identified as having a poor prognosis. Their FTM was 43%, compared with 87% for all other patients combined (P = 0.002). Based on this analysis, we conclude that limited chemotherapy in combination with radiation therapy can yield results similar to programs that use more chemotherapy for all patients with IIIA disease and for most patients with stage IIIB. However, patients with tumor burdens which include pelvic disease and B symptoms require a different approach.

Adult↗
PubMed1988

ChlVPP--an effective and well-tolerated alternative to MOPP therapy for Hodgkin's disease.

The substitution of chlorambucil for nitrogen mustard and vinblastine for vincristine has been suggested to be an equally effective and well-tolerated variation of the MOPP regimen (mechlorethamine, vincristine, procarbazine, and prednisone). We treated 76 patients with advanced (i.e., Stage III, IV, or II with bulky mediastinal mass) or recurrent Hodgkin's disease with chlorambucil 6 mg/m2, procarbazine 100 mg/m2, and prednisone 40 mg p.o. daily, all on days 1-14; plus vinblastine 6 mg/m2 i.v. on day 1 and 8 of each 28-day cycle (ChlVPP). There was no maximum dose of the myelosuppressive agents. Patients who had not previously been irradiated received from 2,300 to 4,100 cGY to sites of previously bulky diseases after completing 6 cycles of ChlVPP. ChlVPP was easy to administer (i.e., 87% of patients without previous chemotherapy received greater than or equal to 80% of the planned doses of myelosuppressive drugs) and was generally well tolerated, with only occasional vomiting from procarbazine and phlebitis from vinblastine. In patients without previous chemotherapy, 49 (76%) achieved a complete remission (CR) and 7 (11%) a stable partial remission (i.e., residual, stable radiographic abnormality). With a maximum follow-up of 4 years, only one CR has relapsed for an actuarial CR durability of 97%. ChlVPP with consolidative radiation therapy to sites of bulky disease is effective in advanced Hodgkin's disease and, compared with most other available regimens, is extremely well tolerated.

Adolescent↗
PubMedDate not supplied

Radiotherapy alone for lymphocyte-predominant Hodgkin's disease.

PURPOSE: The purpose of the study was to analyze the results with radiotherapy alone in a select group of asymptomatic adults with nonbulky, early-stage lymphocyte-predominant Hodgkin's disease. PATIENTS AND METHODS: Between 1963 and 1995, 36 patients with nonbulky stage IA (N = 27) or IIA (N = 9) supradiaphragmatic (N = 27) or subdiaphragmatic (N = 9) lymphocyte-predominant Hodgkin's disease were treated with radiotherapy alone. Eleven of the patients underwent laparotomy. Limited-field radiotherapy involving only one side of the diaphragm and extended-field radiotherapy encompassing both sides of the diaphragm were used in 28 and 8 cases, respectively. Median dose to involved areas was 40.0 Gy given daily in 20 2.0-Gy fractions. Salvage treatmentconsisted of MOPP (mechlorethamine, vincristine, prednisone, procarbazine), CVPP/ABDIC (cyclophosphamide, vinblastine, procarbazine and prednisone/doxorubicin, bleomycin, dacarbazine, lomustine, and prednisone), or ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy and/or involved-field radiotherapy. RESULTS: Median follow-up was 8.8 years (range, 3.0-34.4 years). None of the 15 patients with supradiaphragmatic disease who received limited-field radiotherapy to regions that did not include the mediastinal or hilar nodes subsequently experienced relapse there. Only one of 20 patients who received supradiaphragmatic limited-field radiotherapy alone experienced relapse in the paraaortic nodes or spleen. The 5-year relapse-free and overall survival rates for the 20 patients with stage IA lymphocyte-predominant Hodgkin's disease treated with involved-field or regional radiotherapy were 95% and 100%, respectively. There were no cases of severe or life-threatening cardiac toxicity. No solid tumors have been observed in-field in patients treated with limited-field radiotherapy, even though they have been followed up longer than those treated with extended-field radiotherapy (median follow-up, 11.6 vs 5.5 years); two solid tumors have developed in-field in patients who received extended-field radiotherapy. DISCUSSION: Involved-field or regional radiotherapy alone may be adequate in stage IA lymphocyte-predominant Hodgkin's disease patients. Longer follow-up will help to more clearly define the risks of cardiac toxicity and solid tumors that result from involved-field or regional radiotherapy, which appear to be low based on follow-up to date.

Adolescent↗
PubMed1982

Cutaneous T-cell lymphoma: clinicopathological relationships, therapy and survival in ninety-two patients.

Clinicopathological findings, methods of treatment and survival in ninety-two patients with cutaneous T-cell lymphoma (CTCL) (eighty-five mycosis fungoides and seven Sézary syndrome), seen in the Leiden University Hospital between 1974 and 1980, are reported. All patients were staged and treatment was given accordingly. Patients without signs of extracutaneous disease (74%) were treated with eigher total-skin electron-beam irradiation (E beam), topical mechlorethamine (HN2) or PUVA. Topical HN2 and E beam had an equal effect on survival. Electron-beam induced a higher number of initial complete remissions than HN2, but fewer patients relapsed while on maintenance treatment with HN2. In the patients with lymph node and/or visceral involvement, E beam followed by systemic chemotherapy--cyclophosphamide, vincristin (Oncovin) and prednisone (COP)--gave better results than topical therapy or COP alone. Survival was influenced most by the type of skin lesion, the presence or absence of lymph node and/or visceral involvement, and the ability to induce a complete remission initially.

Adult↗
PubMed2007

Bifunctional alkylating agent-induced p53 and nonclassical nuclear factor kappaB responses and cell death are altered by caffeic acid phenethyl ester: a potential role for antioxidant/electrophilic response-element signaling.

Bifunctional alkylating agents (BFA) such as mechlorethamine (nitrogen mustard) and bis-(2-chloroethyl) sulfide (sulfur mustard; SM) covalently modify DNA and protein. The roles of nuclear factor kappaB (NF-kappaB) and p53, transcription factors involved in inflammatory and cell death signaling, were examined in normal human epidermal keratinocytes (NHEK) and immortalized HaCaT keratinocytes, a p53-mutated cell line, to delineate molecular mechanisms of action of BFA. NHEK and HaCaT cells exhibited classical NF-kappaB signaling as degradation of inhibitor protein of NF-kappaBalpha (IkappaBalpha) occurred within 5 min after exposure to tumor necrosis factor-alpha. However, exposure to BFA induced nonclassical NF-kappaB signaling as loss of IkappaBalpha was not observed until 2 or 6 h in NHEK or HaCaT cells, respectively. Exposure of an NF-kappaB reporter gene-expressing HaCaT cell line to 12.5, 50, or 100 muM SM activated the reporter gene within 9 h. Pretreatment with caffeic acid phenethyl ester (CAPE), a known inhibitor of NF-kappaB signaling, significantly decreased BFA-induced reporter gene activity. A 1.5-h pretreatment or 30-min postexposure treatment with CAPE prevented BFA-induced loss of membrane integrity by 24 h in HaCaT cells but not in NHEK. CAPE disrupted BFA-induced phosphorylation of p53 and p90 ribosomal S6 kinase (p90RSK) in both cell lines. CAPE also increased nuclear factor E2-related factor 2 and decreased aryl hydrocarbon receptor protein expression, both of which are involved in antioxidant/electrophilic response element (ARE/EpRE) signaling. Thus, disruption of p53/p90RSK-mediated NF-kappaB signaling and activation of ARE/EpRE pathways may be effective strategies to delineate mechanisms of action of BFA-induced inflammation and cell death signaling in immortalized versus normal skin systems.

Alkylating Agents↗
PubMed2000

Repair of intermediate structures produced at DNA interstrand cross-links in Saccharomyces cerevisiae.

Bifunctional alkylating agents and other drugs which produce DNA interstrand cross-links (ICLs) are among the most effective antitumor agents in clinical use. In contrast to agents which produce bulky adducts on only one strand of the DNA, the cellular mechanisms which act to eliminate DNA ICLs are still poorly understood, although nucleotide excision repair is known to play a crucial role in an early repair step. Using haploid Saccharomyces cerevisiae strains disrupted for genes central to the recombination, nonhomologous end-joining (NHEJ), and mutagenesis pathways, all these activities were found to be involved in the repair of nitrogen mustard (mechlorethamine)- and cisplatin-induced DNA ICLs, but the particular pathway employed is cell cycle dependent. Examination of whole chromosomes from treated cells using contour-clamped homogenous electric field electrophoresis revealed the intermediate in the repair of ICLs in dividing cells, which are mostly in S phase, to be double-strand breaks (DSBs). The origin of these breaks is not clear since they were still efficiently induced in nucleotide excision and base excision repair-deficient, mismatch repair-defective, rad27 and mre11 disruptant strains. In replicating cells, RAD52-dependent recombination and NHEJ both act to repair the DSBs. In contrast, few DSBs were observed in quiescent cells, and recombination therefore seems dispensable for repair. The activity of the Rev3 protein (DNA polymerase zeta) is apparently more important for the processing of intermediates in stationary-phase cells, since rev3 disruptants were more sensitive in this phase than in the exponential growth phase.

Antineoplastic Agents, Alkylating↗
PubMed2000

Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis.

BACKGROUND AND OBJECTIVES: Skin lesions in Langerhans cell histiocytosis (LCH) are often painful and difficult to treat. Topical application of nitrogen mustard (0.02% mechlorethamine hydrochloride, mustine), an alkylating cytostatic agent, has been shown to be effective. There is, however, concern about potentially harmful long term side effects. STUDY DESIGN: In a retrospective study 20 children with LCH (average extent of initial skin involvement: 16.4% body surface) were followed up for an average of 8.3 years after completion of topical mustine therapy. They had received a total of 34 courses (mean duration 14.2 weeks) of topical mustine. Disease status on follow up was assessed according to the Histiocyte Society classification. RESULTS: After mustine was introduced, 16 patients were able to discontinue systemic steroids and/or chemotherapy. Topical mustine was well tolerated in 18 patients, but two developed irritant dermatitis. On follow up, the disease was inactive in 10 patients. Among the children with active disease, six had mild skin disease and four had progressive disease, two of them with skin lesions unresponsive to mustine treatment. Scars confined to areas of formerly active skin disease were found in six patients. There was no evidence of premalignant or malignant skin disease in the treated areas. CONCLUSION: Topical mustine is an effective and safe treatment for skin disease in most children with LCH. Residual scarring was probably a result of the disease itself rather than to mustine. Although no evidence of skin cancer was found in this study, continued long term follow up is advisable.

Administration, Topical↗
PubMed1975

67Ga citrate distribution following whole-body irradiation or chemotherapy.

Whole-body retention, organ distribution, excretion, and serum binding of 67Ga were evaluated in rats under normal conditions and following whole-body gamma irradiation, vincristine sulfate, or mechlorethamine. The results suggest that both irradiation and chemotherapy lead to reduced whole-body retention of injected radiogallium, explained in part by an alteration in the serum binding of gallium. Recognition of these findings should be considered in interpreting decreased tumor concentration of gallium in patients following radiotherapy or chemotherapy.

Animals↗
PubMed1980

The radiologic appearance of chemical pleurodesis.

Intrapleural instillation of drugs (chemical pleurodesis) was performed in 57 patients with malignant pleural effusions or recurrent pneumothorax. Agents used included mechlorethamine hydrochloride (nitrogen mustard), quinacrine hydrochloride (Atabrine), tetracycline, and others. The most frequent finding on chest radiographs (56%) was multiple loculated air-fluid levels, an appearance simulating an empyema. Resolution of these changes occurred in one to three weeks. Late sequelae included pleural thickening (63%) or the development of a severe fibrothorax. In the majority of the six patients treated for recurrent pneumothoraces, the radiographic appearance returned to normal. The appearance of a new air-fluid level following withdrawal of the chest tube in one patient indicated a complicating empyema.

Adolescent↗
PubMed1993

Role of xanthine oxidase in reperfusion injury of ischemic skeletal muscles in the pig and human.

We investigated whether xanthine oxidase (XO) is a major source of oxygen-derived free radicals (oxy-radicals) in the pig and human skeletal muscles. It was observed that xanthine dehydrogenase and XO activities in nonischemic pig latissimus dorsi (LD) and gracilis muscles and human LD and rectus abdominis (RA) muscles were < 0.5 mU/g wet wt. The pig LD muscle hypoxanthine content increased significantly from 0.33 +/- 0.02 to 2.33 +/- 0.44 mumol/g dry wt after 5 h of warm ischemia, but the muscle uric acid content remained unchanged up to 2 h of reperfusion. Similarly, the hypoxanthine content in the human LD and RA muscles increased from 0.33 +/- 0.03 to 0.84 +/- 0.23 mumol/g dry wt after 2.0-3.5 h of warm ischemia, and the muscle uric acid content remained unchanged at the end of 15-90 min of reperfusion. Furthermore, 5 days of allopurinol treatment (25 mg/kg iv twice daily) starting 2 days before ischemia or 3 days of oxypurinol treatment (25 mg/kg iv twice daily) starting 15 min before reperfusion did not attenuate the extent of skeletal muscle necrosis in pig LD muscles subjected to 5 h of ischemia and 48 h of reperfusion. However, deferoxamine treatment (250 mg/kg iv twice daily) starting before or after ischemia, as described above, significantly reduced the extent of pig LD muscle necrosis. Finally, at 2 and 48 h of reperfusion significantly higher muscle neutrophil contents were seen in ischemic than in nonischemic control pig LD muscles. Neutrophil depletion with mechlorethamine (0.75 mg/kg iv) significantly reduced the extent of necrosis in pig LD muscles. These observations indicate that XO is not a major source of oxy-radicals in ischemia/reperfusion injury in the pig gracilis and LD muscles and human RA and LD muscles.

Adult↗