A 34K SNP genotyping array for Populus trichocarpa: design, application to the study of natural populations and transferability to other Populus species.

Genetic mapping of quantitative traits requires genotypic data for large numbers of markers in many individuals. For such studies, the use of large single nucleotide polymorphism (SNP) genotyping arrays still offers the most cost-effective solution. Herein we report on the design and performance of a SNP genotyping array for Populus trichocarpa (black cottonwood). This genotyping array was designed with SNPs pre-ascertained in 34 wild accessions covering most of the species latitudinal range. We adopted a candidate gene approach to the array design that resulted in the selection of 34 131 SNPs, the majority of which are located in, or within 2 kb of, 3543 candidate genes. A subset of the SNPs on the array (539) was selected based on patterns of variation among the SNP discovery accessions. We show that more than 95% of the loci produce high quality genotypes and that the genotyping error rate for these is likely below 2%. We demonstrate that even among small numbers of samples (n = 10) from local populations over 84% of loci are polymorphic. We also tested the applicability of the array to other species in the genus and found that the number of polymorphic loci decreases rapidly with genetic distance, with the largest numbers detected in other species in section Tacamahaca. Finally, we provide evidence for the utility of the array to address evolutionary questions such as intraspecific studies of genetic differentiation, species assignment and the detection of natural hybrids.

Indicators of homologous recombination deficiency in breast cancer and association with response to neoadjuvant chemotherapy.

BACKGROUND: Tumors with homologous recombination deficiency (HRD), such as BRCA1-associated breast cancers, are not able to reliably repair DNA double-strand breaks (DSBs) and are therefore highly sensitive to both DSB-inducing chemotherapy and poly (ADP-ribose) polymerase inhibitors. We have studied markers that may indicate the presence of HRD in HER2-negative breast cancers and related them to neoadjuvant chemotherapy response. PATIENTS AND METHODS: Array comparative genomic hybridization (aCGH), BRCA1 promoter methylation, BRCA1 messenger RNA (mRNA) expression and EMSY amplification were assessed in 163 HER2-negative pretreatment biopsies from patients scheduled for neoadjuvant chemotherapy. RESULTS: Features of BRCA1 dysfunction were frequent in triple-negative (TN) tumors: a BRCA1-like aCGH pattern, promoter methylation and reduced mRNA expression were observed in, respectively, 57%, 25% and 36% of the TN tumors. In ER+ tumors, a BRCA2-like aCGH pattern and the amplification of the BRCA2 inhibiting gene EMSY were frequently observed (43% and 13%, respectively) and this BRCA2-like profile was associated with a better response to neoadjuvant chemotherapy. CONCLUSIONS: Abnormalities associated with BRCA1 inactivation are present in about half of the TN breast cancers but were not predictive of chemotherapy response. In ER+/HER2- tumors, a BRCA2-like aCGH pattern was predictive of chemotherapy response. These findings should be confirmed in independent series.

Molecular subtypes of breast cancer and amplification of topoisomerase II alpha: predictive role in dose intensive adjuvant chemotherapy.

Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour. In a retrospective analysis, we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a randomised study of adjuvant high-dose chemotherapy in breast cancer. In addition, the topoisomerase II alpha (TOP2A) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation. 411 of the 753 tumours (55%) were classified as luminal-like, 137 (18%) as basal-like and 205 (27%) as human epithelial receptor type 2 (HER2) amplified. The basal-like tumours were defined as having no expression of ER and HER2; 98 of them did express epidermal growth factor receptor and/or cytokeratin 5/6. The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups. From the 194 HER2-positive tumours, 47 (24%) were shown to harbour an amplification of TOP2A. Patients with an HER2-amplified tumour randomised to the high-dose therapy arm did worse than those in the conventional treatment arm, possibly caused by the lower cumulative anthracycline dose in the high-dose arm. The tumours with a TOP2A amplification contributed hardly to this difference, suggesting that TOP2A amplification is not the cause of the steep dose-response curve for anthracyclines in breast cancer. Possibly, the difference of the cumulative dose of only 25% between the treatment arms was insufficient to yield a survival difference.

[The "quality house pediatric oncology" as an instrument for improving the performance of the trial centers]. / Das Qualitätshaus als Instrument zur Leistungsverbesserung von Studienzentralen der Pädiatrischen Onkologie und Hämatologie.

The project group "Central Trial Support" of the German Competence Network Pediatric Oncology and Haematology supports the members of the Society of Pediatric Oncology and Haematology in their effort to cope with the growing statutory, ethical and administrative requirements for therapy optimization studies (investigator-initiated, non-profit clinical trials). By these quality improvement measures the studies will become more revisable and reliable, but at the same time their processing will become more and more complex. The basic instrument of the project group "Central Trial Support" will be the so-called "Quality House" which has been built up in order to improve the performance of the associated study centres and to help put a systematic quality management system into practice. The "Quality House Pediatric Oncology" comprises detailed descriptions of the activities of all trial center co-workers. Its process map details all operational sequences which constitute an efficiently performing trial center. The so-called value adding processes are explained step by step, and the associated specific tasks are assigned to each respective co-worker. At each process step, the person in charge will have explanatory descriptions at her/his disposal and - if necessary - further problem solving means as well as references to possible optimization measures (e. g. Standard Operating Procedures and other documents). The German Competence Network Pediatric Oncology and Haematology will be implementing this electronic quality management system in trial centers which will convince both sponsors and authorities of the compliance with requirements and standards.

[Quality management within the competence network of paediatric oncology and haematology]. / Qualitätssicherung im Kompetenznetz Pädiatrische Onkologie und Hämatologie.

The competence network paediatric oncology and haematology aims at improving the structure of paediatric oncology and haematology as a whole focussing in particular on the quality of clinical trials and study centres. This implicates the following measures: (1) Employment of research and trial assistants in order to improve the quality of documentation and study management in the participating hospitals. (2) Building up of an Internet portal to provide medical information for non-professionals, for patients and their families as well as for health professionals. (3) The project "Study Assistance" supports study centers during the process of writing and examining new treatment protocols so that they are in compliance with the Good Clinical Practice criteria, formal criteria and statutory provisions. It presently works on a structural standardisation of study protocols and case record forms in order to improve their usability. In addition, the working group "Quality Assurance in GPOH Study Centres" is engaged in developing a quality management system for study centers.

Functional identification of secondary mutations inducing autonomous growth in synergy with a truncated interleukin-3 receptor: implications for multi-step oncogenesis.

OBJECTIVE: A truncated common beta chain (Deltabeta(C)) of the interleukin-3 (IL-3) receptor complex was previously identified as a key factor in inducing autonomous growth of IL-3-independent mutants. Expression of Deltabeta(C) in IL-3-dependent hematopoietic cells does not result in immediate factor-independent growth, but increases the frequency of obtaining autonomous mutants by three to four orders of magnitude. This study was designed to delineate the mechanisms by which Deltabeta(C) increases the frequency to autonomous growth. DESIGN AND METHODS: Retroviral vectors were used to express Deltabeta(C) into IL-3-dependent myeloid cells, which were then tested for factor-independent growth. To determine if secondary genetic events were required for conversion to autonomous growth, elements of the Cre-loxP recombinant system were used to excise Deltabeta(C) in factor-independent clones. RESULTS: Excision of Deltabeta(C) in factor-independent clones revealed two types of phenotypes: reversion to factor-dependent growth (1/8) or continued IL-3-dependent growth (7/8). Analysis of cells that remained factor independent revealed constitutive activation of STAT5, not observed in factor-dependent revertants. Analysis of revertant cells demonstrated the presence of interacting secondary mutations that synergize with Deltabeta(C)-induced proliferation. A cysteine residue within the truncated extracellular domain of Deltabeta(C) was also found to be required for its oncogenic potential, supporting a model of dimerization for receptor activation. CONCLUSIONS: The high incidence of obtaining factor-independent mutants from cells expressing Deltabeta(C) results from the selection of mutations that either complement Deltabeta(C) expression to promote proliferation or that singly or in synergy with other secondary mutations negate the requirement of Deltabeta(C) expression for proliferation.

Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein.

The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in a pediatric cancer and occurs in approximately 25% of common acute lymphoblastic leukemia (cALL) cases. This rearrangement results in the in frame fusion of the 5'-region of the ETS-related gene, TEL (ETV6), to almost the entire acute myeloid leukemia 1 (AML1) (also called CBFA2 or PEBP2AB1) locus and expression of the TEL-AML1 chimeric protein. Although AML1 stimulates transcription, TEL-AML1 functions as a repressor of some AML1 target genes. In contrast to the wild type AML1 protein, both TEL and TEL-AML1 interact with N-CoR, a component of the nuclear receptor corepressor complex with histone deacetylase activity. The interaction between TEL and N-CoR requires the central region of TEL, which is retained in TEL-AML1, and TEL lacking this domain is impaired in transcriptional repression. Taken together, our results suggest that TEL-AML1 may contribute to leukemogenesis by recruiting N-CoR to AML1 target genes and thus imposing an altered pattern of their expression.

The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways.

Inappropriate activation of Abl family kinases plays a crucial role in different human leukaemias. In addition to the well known oncoproteins p190Bcr-Abl and p210Bcr-Abl, Tel-Abl, a novel fusion protein resulting from a different chromosomal translocation, has recently been described. In this study, the kinase specificities of the Bcr-Abl and Tel-Abl proteins were compared to the physiological Abl family kinases c-Abl and Arg (abl related gene). Using short peptides which correspond to the target epitopes in known substrate proteins of Abl family kinases, we found a higher catalytic promiscuity of Bcr-Abl and Tel-Abl. Similar to Bcr-Abl, Tel-Abl was found in complexes with the adapter protein CRKL. In addition, c-Crk II and CRKL are tyrosine phosphorylated and complexed with numerous other tyrosine phosphorylated proteins in Tel-Abl expressing Ba/F3 cells. GTPase analysis with a Ras-GTP-specific precipitation assay showed constitutive elevation of GTP-loaded Ras in cells expressing the leukaemic Abl proteins. The mitogenic MAPK/Erk kinases as well as Akt/PKB, a kinase implicated to negatively regulate apoptosis, were also constitutively activated by both Bcr-Abl and Tel-Abl. The results indicate that the leukaemic Abl-fusion proteins have catalytic specificities different from the normal kinases c-Abl and Arg and that Tel-Abl is capable to activate at least some pathways which are also upregulated by Bcr-Abl.

Nephrotoxic and peroxidative potential of meropenem and imipenem/cilastatin in rat and human renal cortical slices and microsomes.

BACKGROUND: Carbapenems are a relatively new class of beta-lactam antibiotics characterized by a broad spectrum of antibacterial activity. Meropenem (MER), a new carbapenem has shown a lower nephrotoxic potential compared to imipenem (IMI). IMI is used in a fixed one-to-one combination with the nephroprotective agent cilastatin (CIL). The present studies examined whether MER and IMI/CIL produce peroxidative and nephrotoxic alterations including oxidative changes in rat and human renal cortical slices and microsomes. MATERIALS AND METHODS: Untreated slices and microsomes were incubated in vitro for various periods of time in phosphate-buffered media containing various concentrations of MER, IMI/CIL or for comparison cephaloridine (CPH). Lipid peroxidation was monitored by the determination of malondialdehyde (MDA) in incubation media and slices in the presence or absence of antioxidants. Total glutathione, oxidized glutathione (GSSG), pyruvate-stimulated gluconeogenesis and paraaminohippurate (PAH) accumulation were measured in slices. RESULTS: In rat renal cortical slices, MER, IMI/CIL and CPH induced a time- and concentration-dependent MDA production (content in incubation media plus slices). 5 mM MER, 5 mM IMI/CIL and 3 mM CPH were the lowest concentrations which caused a significant MDA production after 3 hs compared to control (control 61.5+/-15.3 nmol MDA/g tissue, MER 75.4+/-10.9, p<0.001; control 48.0+/-8.7, IMI/CIL 65.1+/-11.7, p<0.001; control 61.5+/-15.3, CPH 113.0+/-28.2, p<0.001). 20 mM MER, 20 mM IMI/CIL and 12 mM CPH revealed marked MDA production after 3 hs in human renal cortical slices (control 29.8+/-4.2 nmol MDA/g tissue, MER 49.4+/-8.7, p<0.01; control 27.6+/-7.0, IMI/CIL 68.3+/-9.9, p<0.001; control 32.5+/-7.7, CPH 93.8+/-31.6, p<0.001) and in human renal microsomes (control 1.0+/-0.9 nmol MDA/mg protein, MER 2.9+/-1.0, p<0.05; IMI/CIL 6.8+/-2.2, p<0.001; CPH 8.4+/-2.2, p<0.001), respectively. The corresponding MDA production was about 2-fold higher in rat renal cortical slices and almost the same in rat renal microsomes. Antioxidants reduced the MER-induced increase in MDA content in rat renal cortical slices by 48% (alpha-tocopherol, 10(-4) M), 72% ((+)-cyanidanol-3, 10(-5) M) and 100% (DPPD, N, N'-diphenyl-p-phenylendiamine, 10(-6) M). In rat renal cortical slices, MER and IMI/CIL induced an increase up to 50% in the content of GSSG and a corresponding %-decrease in reduced glutathione (GSH). In rat renal cortical slices, MER and IMI/CIL induced a time- and concentration-dependent decrease in PAH accumulation and gluconeogenesis. PAH accumulation was already reduced by 5 mM MER after 1 h (control slice to medium ratio 18.3+/-6.8, MER 10.7+/-1.9, p<0.05) and by 10 mM IMI/CIL after 3 h (control 16.9+/-5.6, IMI/CIL 5.5+/-1.3, p<0.001). Pyruvate-stimulated gluconeogenesis after 3 hs was already reduced by 2.5 mM MER (control 5.7+/-2.1 micromol glucose/g tissue/h, MER 3.9+/-1.1, p<0.05) and by 10 mM IMI/CIL (control 5.7+/-2.1, IMI/CIL 2.8+/-1.0, p<0.001). CONCLUSION: Thus, MER and IMI/CIL (at concentrations more than 10-fold higher as peak plasma concentrations achieved in humans) revealed an oxidative change (depletion of GSH, production of GSSG), a peroxidative potential (production of MDA) and a nephrotoxic potential (reduction in pyruvate-stimulated gluconeogenesis and PAH accumulation). Human kidney seems to be less susceptible to beta-lactam antibiotic-induced lipid peroxidation than rat kidney.

Haemopoietic transformation by the TEL/ABL oncogene.

Rare, novel forms of activated ABL kinase, the result of a fusion between TEL (or ETV6, a member of the ETS transcription factor family), and the non-receptor tyrosine kinase ABL, have been identified. We have analysed the TEL/ABL fusion protein (type A) cloned from an acute lymphoblastic leukaemia patient. In contrast to a second TEL/ABL fusion (type B) identified in two cases of myeloid leukaemia, the portion of TEL contained in the type A TEL/ABL fusion was smaller and did not contain a potential Grb2 binding site. The type A TEL/ABL cDNA we used in this study encoded a 155 kD protein with elevated tyrosine kinase activity and was responsible for the phosphorylation of a number of proteins in vivo. Its expression in factor-dependent murine haemopoietic precursor cells efficiently converted these cells to factor independence for both survival and growth. These cells continued to express high levels of myc mRNA after growth factor depletion. We also demonstrated that type A TEL/ABL self-associated in stably expressing haemopoietic cells. Although the TEL portion of the TEL/ABL fusion protein has no sequence similarity to that of BCR in the BCR/ABL protein, all forms of these fusion proteins contain a structure implicated in oligomerization. Our results support the conclusion that the protein interaction domain of BCR and TEL, but not the Grb2 binding site, are the important functional components in the activation of ABL kinase in haemopoietic discase.

The second ETV6 allele is not necessarily deleted in acute leukemias with a ETV6/ABL fusion.

The ETV6 (TEL) locus at chromosome band 12p 13 is a major site of translocations in acute leukemia, particularly in childhood acute lymphoblastic leukemia (ALL). In cases with translocations involving ETV6, the normal ETV6 allele is often deleted. In addition, loss of heterozygosity of ETV6 is frequently observed in childhood'ALL. Thus, it has been suggested that ETV6 may have an anti-oncogenic role to play, in addition to its oncogenic role. We have described an unusual case of ALL in which ETV6 is found fused to the ABL gene; ABL is normally activated by fusion to the BCR gene in the 9:22 translocation. We expanded the primary cells from this ETV6/ABL rearranged case of ALL in SCID animals and analyzed them for expression of both ETV6/ABL and the normal ETV6 mRNA. We found that both the rearranged and normal ETV6 mRNAs are expressed in the expanded cell population. Furthermore, sequence analysis of the ETV6 PCR product revealed no point mutations which would influence the amino acid sequence. Thus, deletion of the second ETV6 allele is not necessary for the transformation to leukemia by ETV6/ABL.

Toxic effect of concomitant administration of cyclosporin A and acyclovir on renal function and morphology in rats.

The immunosuppressive agent cyclosporin A (CyA) and the antiviral drug acyclovir may cause renal functional impairment. CyA-induced immunosuppression increases the rate of viral infections. Therefore we were interested to determine whether short-term co-administration of CyA and acyclovir involves an increased nephrotoxic risk. Male Wistar rats were treated with CyA (20 mg/kg body wt., s.c., once daily for 8 days), acyclovir (15 mg/kg body wt., s.c., 3-times daily for the last 5 days) or a combination of CyA and acyclovir. Blood levels of CyA were determined after a single dose. Urine was monitored for volume, osmolality, total protein and N-acetyl-beta-D-glucosaminidase (beta-NAG). Concentrations of blood urea nitrogen (BUN) and plasma-creatinine were determined (day 9). Renal cortical slices were monitored for accumulation of weak organic acids (para-aminohippurate, PAH) and bases (tetra-ethylammonium, TEA) and for malondialdehyde (MDA) content. Renal histology was also examined. CyA induced a decrease in body and kidney weight, in urine osmolality and in the excretion of total protein. Plasma-creatinine and BUN as well as MDA content of renal tissues were increased by CyA. Acyclovir alone did not induce significant changes. In comparison to CyA values, urine volume and beta-NAG excretion were enhanced and TEA accumulation depressed by the concomitant administration of CyA and acyclovir. CyA- or acyclovir-treatment alone did not result in significant morphological changes. In the group co-administered CyA/acyclovir, the kidneys showed mild to moderate signs of tubulopathy. Short-term co-administration of CyA and acyclovir was concluded to have possibly increased nephrotoxic potential.

[Disturbed neutrophil activation in pneumonia during medicinal immunosuppression]. / Gestörte Neutrophilenrekrutierung bei Pneumonie im Rahmen einer medikamentösen Immunsuppression.

BACKGROUND: In medically immunosuppressed patients with pneumonia, the BAL cell differential and neutrophils secretion products were determined and compared to patients with pneumonia without defined immunodeficiency in order to define a possibly deficient neutrophil function. PATIENTS AND METHODS: Forty-eight medically immunosuppressed patients were studied: 24 pts. after renal transplantation receiving threefold immunosuppression (cyclosporine, azathioprine, prednisolone), 14 pts. with non-Hodgkin-lymphoma receiving polychemotherapy and 10 pts. with rheumatologic disorders (rheumatoid arthritis n = 3, M. Wegener n = 5 und SLE n = 2) receiving cyclophosphamide or methotrexate. For comparison, 116 patients without defined immunodeficiency and pneumonia and 16 healthy adults were studied. In addition to the cell differential the BALF concentrations of the neutrophil degranulation products myeloperoxidase (MPO) and lactoferrin were determined using immunoluminometric assays. For identification of microorganisms semiquantitative cultures were used. RESULTS: Neutrophilia > 5% in BAL was present in only 36% of the immunosuppressed pts. in contrast to 91.3% of the immunocompetent pts. (p < 0.01). The same pathogen was found in 14 pts. of each group, so that a pathogen matched comparison was possible. The neutrophil percentage and the BALF concentration of lactoferrin was significantly lower in the immunosuppressed group. In blood there was no difference with regard to the neutrophil count between the groups. CONCLUSIONS: BAL characteristics of immunosuppressed pts. are different from those of immunocompetent pts. with pneumonia. The pathogen-matched comparison proved that this is not due to different pathogens. Medically immunosuppressed patients with pneumonia exhibit a disturbed neutrophil recruitment. A neutrophil percentage < 5% in BAL of medically immunosuppressed patients does not preclude a bacterial infection.

Sequential mutations in the interleukin-3 (IL3)/granulocyte-macrophage colony-stimulating factor/IL5 receptor beta-subunit genes are necessary for the complete conversion to growth autonomy mediated by a truncated beta C subunit.

An amino-terminally truncated beta C receptor (beta C-R) subunit of the interleukin-3 (IL3)/granulocyte-macrophage colony-stimulating factor/IL5 receptor complex mediates factor-independent and tumorigenic growth in two spontaneous mutants of a promyelocytic cell line. The constitutive activation of the JAK2 protein kinase in these mutants confirms that signaling occurs through the truncated receptor protein. Noteworthily, in addition to a 10-kb deletion in the beta C-R subunit gene encoding the truncated receptor, several secondary and independent mutations that result in the deletion or functional inactivation of the allelic beta C-R subunit and the closely related beta IL3-R subunit genes were observed in both mutants, suggesting that such mutations are necessary for the full oncogenic penetrance of the truncated beta C-R subunit. Reversion of these mutations by the expression of the wild-type beta C-R in the two mutants resulted in a fivefold decrease in cloning efficiency of the mutants in the absence of IL3, confirming a functional interaction between the wild-type and truncated proteins. Furthermore, expression of the truncated beta C-R subunit in factor-dependent myeloid cells did not immediately render the cells autonomous but increased the spontaneous frequency to factor-independent growth by 4 orders of magnitude. Implications for both leukemogenic progression and receptor-subunit interaction and signaling are discussed.

[Generalized nocardiosis with meningoencephalitis in a nonimmunosuppressed female patient]. / Generalisierte Nokardiose mit Meningoenzephalitis bei einer nicht-immunsupprimierten Patientin.

Four weeks after an attack of pneumonia of unknown aetiology a 40-year-old woman was hospitalized because of a nonpurulent, predominantly basal meningoencephalitis and infratentorial abscesses. She had dysarthria, mild right-sided motor hemiparesis and central paresis affecting the 7th cranial nerve. An area of fluctuating resistance, about 3 cm in diameter, was noticed over the left thigh. Serology indicated inflammatory disease, but there was no immunodeficiency. The CSF showed lymphocytic pleocytosis with mild protein increase but no evidence of infective agent. As tubercular meningitis was suspected she was treated with rifampicin (300 mg i.v. twice daily), isoniazid (300 mg i.v. once daily), streptomycin (800 mg i.m. once daily), cefotaxime (2.0 g i.v. three times daily), fluconazole (200 mg i.v. once daily) and dexamethasone (16-8-8 mg i.v.). She suddenly died two days after admission, probably as the result of central regulatory failure. Generalized nocardiosis involving lung, subcutaneous tissue and brain was revealed at autopsy. Although nocardiosis occurs predominantly in patients under immunosuppression, this infection should be considered in the differential diagnosis of treatment-resistant pneumonia and meningoencephalitis without obvious predisposition.

Nephrotoxicity of acyclovir and cis-diamminedichloroplatinum(II)--effect of co-administration in rats.

The effect of co-administration of acyclovir and cis-diamminedichloroplatinum(II) (cisplatin) on nephrotoxicity in male Wistar rats was investigated. Animals received acyclovir (15 mg/kg body weight, s.c., three times per day for 5 days) or cisplatin (5 mg/kg body weight, i.p., one single injection) or a combination of both drugs. Acyclovir plasma levels were determined after one single acyclovir s.c. injection. Urines were monitored for volume, pH, osmolality and excretion of N-acetyl-beta-D-glucosaminidase (NAG), lysozyme and total protein. Concentrations of blood urea nitrogen and plasma creatinine were determined on day 6. Renal cortical slices were monitored to assess the accumulation of weak organic bases (tetraethylammonium) and acids (p-aminohippurate). Cisplatin induced a marked increase in the excretion of NAG, lysozyme and total protein and an increase in urine volume, plasma creatinine and blood urea nitrogen. Urine osmolality and accumulation of p-aminohippurate were depressed by cisplatin. Acyclovir treatment alone caused no significant symptoms of nephrotoxicity. Co-administration did not impair renal function more than cisplatin treatment alone, excepting a slight rise in lysozyme excretion on day 6. Short-term antiviral therapy with acyclovir, concomitant to cisplatin treatment, may bring, if at all, a slightly increased nephrotoxic risk.