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Background: Safe and reliable central venous access is critical in the management of children with cancer. A recently described valved catheter (Groshong) requires less frequent flushing to preserve catheter patency, theoretically reducing daily care costs for the catheter as well as lessening the risk of mechanical or infectious complications. This study compared standard Hickman to Groshong catheters in a group of pediatric oncology patients., Study Design: From December 1992 to May 5, 1994, 20 consecutive pediatric oncology patients were randomized by medical record number to receive either a standard dual lumen Hickman (7F) or Groshong (9.5F) catheter. All patients were prospectively followed on a weekly basis and a log was maintained regarding complications and cost of maintenance of the catheter until it was removed., Results: Ten patients received Groshong catheters and ten received Hickman catheters. Total catheter days for each group were similar (Hickman, 2,599 compared with Groshong, 2,389 days). Five Groshong catheters required removal because of mechanical complications and several required daily flushes because of blood backing up into the catheter lumen. When taking into account the cost of associated complications, no differences were noted in daily cost for maintenance between the two catheters., Conclusions: When considering the cost of complications, Groshong catheters were no less expensive to maintain compared with standard Hickman catheters. Furthermore, Groshong catheters malfunctioned more frequently and required a greater number of urokinase instillations for withdrawal occlusion. The use of the Groshong catheter in pediatric oncology patients cannot be supported by the present study.

Biopsies of superficial bladder cancer were analysed to study the relationship between response to epirubicin and the expression of the human topoisomerase II alpha and beta genes. Tissue samples were obtained prior to treatment and a marker tumour was left in the bladder. Transcript levels of both genes were generally lower in biopsies taken following treatment failure. Levels of topoisomerase II mRNA were uniformly lower in tumour tissue than in biopsies of normal tissue.

We review recently published literature on behavioral aspects of asthma, including program descriptions, reviews, and original research reports. Most of the literature on behavioral aspects of asthma has been in the area of self-management, including education, medication use, and peak flow monitoring. Recent studies of these factors have shown promising trends in reducing morbidity and in improving health care utilization outcomes. Medication adherence continues to be problematic, and its complexity is increased when comparing inhaled with oral medications and bronchodilators with anti-inflammatory agents. Psychobiologic factors that have been recently studied include perceptions of airway changes and the role of emotional responses in asthma self-management. Because the behavioral aspects of asthma play such a significant role in asthma treatment, further study is needed to determine how changes in patient behavior can improve patient quality of life.

Given that poor asthma management leads to such devastating rates of morbidity and mortality in this country, efforts must be made to increase the knowledge, skills, and behaviors of persons with asthma. The suggestions and recommendations provided here represent a blend of academic opinion and practical advice on methods to implement an asthma education program. In developing an asthma education program, consideration must be given to what content should be included, how and by whom that content should be taught, and when education should take place. The identification of a key clinical staff member to take the lead in translating these and other asthma education guidelines will be a critical next step for clinicians committed to developing an effective asthma education program.

Topoisomerase II enzymes play an essential role in human DNA metabolism. They are also recognized as primary targets of a number of anti-cancer drugs used in the treatment of breast cancer, which remains a leading cause of cancer-related death in women. While topoisomerase inhibitors have produced significant response rates in this disease, their use has been limited both by toxicity and by the development of resistance. In this article we review the extensive work which has not only increased our understanding of the biochemistry and molecular biology of type II topoisomerases but also enabled more rational drug design. Such knowledge should translate into increased clinical efficacy in the treatment of breast cancer and other malignancies.

Topoisomerase II (Topo II) is an essential enzyme that catalyzes the breakage of double-strand DNA and is the target of several effective anticancer drugs, including the epipodophyllotoxins. The regulatory subunits of the cyclic AMP-dependent protein kinase are differentially expressed in normal and cancer cells. The RIalpha subunit is overexpressed in cells transformed by transforming growth factor-alpha (TGF-alpha) or Ha-ras oncogene. It has been shown that murine cells transformed by Ha-ras become hypersensitive to Topo II-targeting anticancer drugs. In this report we have tested whether any correlation exists between the expression of RIalpha protein and cellular sensitivity of Topo II-targeting drugs. Normal human breast MCF-10A cells and their derivatives overexpressing TGF-alpha, Ha-ras, or the different protein kinase subunits were treated with either Topo II inhibitors, such as etoposide, teniposide, or amsacrine, or with drugs which act independently of Topo II, such as bleomycin. Here we show that MCF-10A TGF-alpha and MCF-10A Ha-ras cells overexpress the RIalpha protein and become hypersensitive to epypodophyllotoxins and amsacrine but not to bleomycin. Direct introduction of the RIalpha gene into MCF-10A induces hypersensitivity to Topo II inhibitor drugs. In contrast, the overexpression of the other protein kinase subunits, RIIbeta or Calpha, does not modify the drug sensitivity of MCF-10A cells. No differences in the mRNA/protein content or in the activity of Topo II were found between hypersensitive cells and parental MCF-10A cells, suggesting that RIalpha may influence drug sensitivity via modulation of events downstream of the Topo II-DNA cleavable complex.

An approach to the preparation of antigen-specific human monoclonal antibodies focuses on mice transgenic for human immunoglobulin gene miniloci; the V gene segments in these miniloci undergo productive rearrangement to yield mouse B cells expressing human immunoglobulin (Ig) chains. The general usefulness of this strategy hinges on whether it is feasible to obtain specific, high-affinity antibodies following immunization of such animals with a variety of antigens. To test this, we have investigated the antigen-specific responses in mice which carry human IgH miniloci (constaining just one or two VH segments) instead of a functional mouse IgH locus. Although serum responses were relatively weak, monoclonal antibodies were readily obtained to all immunogens tested (a hapten, foreign proteins and human lymphoma cells). The affinities of two of the hapten-specific (anti-2-phenyl-oxazol-5-one) antibodies were 60 and 160 nM, values intermediate between what is typically obtained in the primary and secondary response of normal mice. Sequence analysis of the rearranged V genes revealed that junctional events made a major contribution to diversity with a considerable amount of apparently non-templated sequence at the V-D and D-J borders. Somatic hypermutation was also evident within the expressed V gene segments of many of the antigen-specific hybridomas. These findings augur well for the general usefulness of the transgenic approach for the isolation of high-affinity human antibodies to a wide range of antigens and suggests that the miniloci need not be particularly large.

We have shown that a mutant derivative of Chinese hamster ovary CHO-K1 cells, ADR-5, which shows hypersensitivity to topoisomerase II (topo II)-inhibitory drugs, is cross-sensitive to the site-selective cyclic AMP analogue 8-chloro-cyclic AMP. We tested the hypothesis that overexpression of the type I alpha regulatory subunit of protein kinase A may represent a common element conferring hypersensitivity to both topo II inhibitors and 8-chloro-cyclic AMP in ADR-5 cells. We have demonstrated that ADR-5 cells overexpress RI alpha protein, compared to parental CHO-K1 cells. Moreover, retroviral vector-mediated transfer of the RI alpha gene into CHO-K1 cells was able to confer a drug-hypersensitive phenotype similar to that exhibited by ADR-5 cells. Analysis of topo II protein levels and activity revealed no differences between parental and infected cells, suggesting that protein kinase A may be involved in the downstream processing of topo II-mediated events.

Mechanisms of resistance to VP-16 were monitored in a series of sublines of the human testicular teratoma cell line (SuSa) derived following exposure either to fractionated X-irradiation (DXR-10) or to VP-16 using pulsed 24-hr exposures (VP10) or continuous exposure conditions (VPC2, VPC3 and VPC4). Orders of resistance expressed (ranging from 3- to 33-fold based on IC50 values derived from colony forming assays) were comparable with those likely to be encountered clinically. All of these resistant sublines showed some cross-resistance to VCR, and the 3 drug-selected sublines tested also proved cross-resistant to ADR. Resistance was not associated with modified 3H-VP-16 accumulation. However, decreased VP-16-induced SSBs were detectable in all the resistant sublines and a strong positive correlation was noted between the extent of SSB formation and VP-16 resistance by linear regression analysis. Topo II alpha protein content, as judged by Western blotting, was significantly decreased only in the sublines derived by continuous exposure to VP-16, but this was not progressive with increasing levels of resistance expressed. RNase protection assays also showed no significant differences in Topo II alpha expression in the low-level resistant DXR-10 and VP10 sublines, contrasting with the 2-fold decreases identified in the VPC2, VPC3 and VPC4 sublines. Significantly, however, mRNA levels of two alternately spliced Topo II beta mRNAs were markedly decreased (2- to 9-fold) in all the drug-selected resistant sublines. No mutations in consensus ATP-binding sequences or in the DNA-binding region of Topo II alpha were detected by single strand conformational polymorphism analysis. Significant Pgp overexpression was only identified in the most highly resistant sublines VPC3 and VPC4, which both showed 4-fold cross-resistance to VCR. Decreased 3H-VCR accumulation and partial reversal of resistance by VPM (6.6 microM) addition was also identified, consistent with a functional Pgp being overexpressed in these sublines. Modifications of Topo II expression therefore appear to precede Pgp overexpression in this series of sequentially derived VP-16 resistant sublines and to represent the predominant mechanism underlying low level (< 10-fold) resistance.

Sixteen Chinese chronic hepatitis B virus (HBV)-infected patients were treated with recombinant interferon-alpha 2a (rIFN-alpha 2a). Of these, 8 made a response to IFN, with titers of neutralizing antibody of 141-4525 as determined by an antiviral neutralization bioassay. To determine whether the immunogenicity of the IFN was directly linked to the patients' genotype, their genomic DNA was analyzed for the presence of the human IFN-alpha 2a gene. None of the patients possessed the gene for IFN-alpha 2a, but only 50% developed neutralizing antibodies. The hypothesis, therefore, of a direct link between antibody formation and genotype cannot be sustained. Alternative explanations of the immunogenicity of IFN-alpha 2a must be sought.

Purified thermostable alcohol dehydrogenase allozymes ADH-71k and ADH-FCh.D. of Drosophila melanogaster have been compared with the two common enzyme forms ADH-F and ADH-S. Enzyme kinetic parameters for various primary and secondary alcohols were determined under standard conditions used previously. Both ADH-71k and ADH-FCh.D. show ADH-S-like reaction kinetics and Km values, due to retrograde evolution at site 214, Pro-->Ser. Inhibition studies with alcohol dehydrogenase inhibitors pyrazole, 4-methylpyrazole, and cibacron blue 3GA were also performed. Activity measurements on crude extracts of larvae and flies from isogenic lines of ADH-FCh.D. revealed a consistently higher activity than in ADH-71k-containing strains, in contrast to the original strains.

Screening of a human B-cell cDNA library with a topoisomerase II beta gene-specific probe revealed the presence of two distinct forms of topoisomerase II beta cDNA. One form (designated topoisomerase II beta-1), representing the majority of the clones, would encode the topoisomerase II beta amino acid sequence reported recently [Jenkins, J.R. et al. (1992) Nucleic Acids Res., 20, 5587-5592]. The second form (designated topoisomerase II beta-2) would encode a protein containing an additional 5 amino acids inserted after Valine-23 of the topoisomerase II beta-1 protein sequence. The topoisomerase II beta-1 and beta-2 mRNAs were both widely expressed in human cell lines and tissues. Topoisomerase II beta-2 mRNA was expressed at a lower level than that of the beta-1 form, but the relative expression of the two forms varied in different cell types. Analysis of genomic DNA clones revealed that the two forms of topoisomerase II beta mRNA arose via differential splicing. These data indicate that in addition to the closely related topoisomerase II alpha and beta isozymes, there are two forms of topoisomerase II beta mRNA widely expressed in human cells.

The sensitivities and specificities of the IgA and IgG antigliadin antibody and the IgA antireticulin antibody have been compared with the recently described endomysial antibody directed against the basement membrane of smooth muscle in monkey oesophagus. One hundred and seventeen patients with adult coeliac disease (21 untreated), 84 patients with inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis (comprising the disease control group), 47 normal controls and a miscellaneous group of 29 patients, who were selected because of a positive reticulin staining pattern, were investigated. These results were correlated with the degree of abnormality of the intestinal mucosa in patients with adult coeliac disease. Endomysial antibodies were found in all patients with untreated coeliac disease and subtotal villous atrophy and in 47% of patients on a non-strict gluten free diet. One patient on a strict gluten free diet was positive and had partial villous atrophy while all patients in disease control groups were negative. Results were variable with the antireticulin and antigliadin antibodies. Sensitivity and correlation with subtotal villous atrophy in the untreated patients was 100%. It is concluded that the endomysial antibody is superior to other current antibody tests and should be used in preference for the diagnosis of coeliac disease.

Topoisomerases catalyse the interconversion of topological isomers of DNA and have key roles in nucleic acid metabolism. Human cells express two distinct type II topoisomerase isozymes, designated topoisomerase II alpha (170 kDa form) and topoisomerase II beta (180 kDa form). We have isolated cDNA clones encoding the beta isozyme from a human B-cell library. The proposed coding region for the topoisomerase II beta protein is 4,863 nucleotides long and would encode a polypeptide with a calculated M(r) of 182,705. The predicted topoisomerase II beta protein sequence shows striking similarity (72% identical residues) to that of the human alpha isozyme, and homology to topoisomerase II proteins from Drosophila, yeast and bacteria. Regions of greatest amino acid sequence divergence lie at the extreme N-terminus and over a C-terminal domain comprising approximately 25% of the total protein. We have quantified the level of topoisomerase II beta mRNA in a panel of human tumour cell lines of different origin using an RNase protection assay, and compared the level to that of topoisomerase II alpha mRNA. Topoisomerase II beta mRNA was expressed in haemopoietic, epithelial and fibroblast cell lines, although to different extents, with U937 cells (promonocytic leukaemia) showing a particularly high level. There was no obvious relationship in terms of level of expression between the topoisomerase II alpha and beta genes. We have localised the gene encoding topoisomerase II beta protein to chromosome 3p24 in the human genome.

Mutants are invaluable in the study of DNA repair processes. The past 10 years have seen a rapid proliferation of papers describing the isolation of mammalian cell mutants exhibiting DNA repair abnormalities. A variety of DNA-damaging agents, including radiation, alkylating agents and bleomycin, have been used to select mutants. This mini-review will concentrate on radiation (particularly ionizing radiation)-sensitive mutants, whether selected directly on the basis of radiation sensitivity or subsequently found to be cross-sensitive to radiation. Commonly observed DNA repair defects are associated with sensitivity to radiation. For UV-sensitive mutants a defect in the incision step of excision repair is frequently seen. For ionizing radiation-sensitive mutants, the common feature is a defect in the repair of DNA strand breaks. This may take the form of a reduced rate of strand-break rejoining or of a lowering in the fidelity of rejoining. Recent work suggests that the DNA topoisomerases may participate in the repair of DNA strand breaks and that strand breaks induced by both topoisomerase inhibitory drugs and radiation may be repaired by common pathways.

We have isolated, following one-step mutagenesis, a Chinese hamster ovary cell mutant hypersensitive to the intercalating agent, adriamycin (4-fold compared to parental CHO-K1 cells). This agent exerts at least part of its cytotoxic action via inhibition of the nuclear enzyme, topoisomerase II. The mutant, designated ADR-3, showed hypersensitivity to all classes of topoisomerase II inhibitors, including actinomycin D, amsacrine (m-AMSA), etoposide (VP16) and mitoxantrone. ADR-3 cells also showed cross-sensitivity to ionizing radiation, but not to UV light. Cellular accumulation of radiolabeled actinomycin D was similar in parental and mutant cells. At equimolar doses, adriamycin induced more protein-associated DNA single- and double-strand breaks in ADR-3 cells than in CHO-K1 cells. Topoisomerase II activity was elevated to a small but significant degree in ADR-3 cells, and this was reflected in a 1.5-fold higher level of topoisomerase II protein in ADR-3 than in CHO-K1 cells, as judged by Western blotting. ADR-3 cells were hypersensitive to cumene hydroperoxide but cross-resistant to hydrogen peroxide, suggesting possible abnormality in the detoxification of peroxides by glutathione peroxidase or catalase. Glutathione peroxidase activity against hydrogen peroxide was similar in CHO-K1 and ADR-3 cell extracts, but activity against cumene hydroperoxide was evaluated to a small but significant extent in mutant cells. Catalase levels were not significantly different in ADR-3 and CHO-K1 cells. ADR-3 cells were recessive in hybrids with parental CHO-K1 cells with respect to sensitivity to topoisomerase II inhibitors and X-rays, and represent a different genetic complementation group from the previously reported adriamycin-sensitive mutant, ADR-1 [Davies et al., J. Biol. Chem., 263 (1988) 17724-17729].

3H-Imipramine binding was measured in freshly prepared platelet membranes from 47 drug-free major depressives and 46 healthy controls. Where possible, platelet binding in depressed subjects was repeated following treatment. A significant negative correlation was found between Bmax and assay protein concentration and Bmax values were corrected for this effect. Adjusted Bmax was significantly lower (by 14%) in female depressed patients than in female control subjects, and the difference was of similar magnitude premenopausally and postmenopausally. No such difference was found in males. Kd did not differ significantly between depressed and control subjects. Multiple regression analysis confirmed significant effects on Bmax of presence of depressive illness, age (positive correlation), and season (higher in summer). Within the depressed sample, Bmax was significantly lower in those subjects with obsessional features. Endogenicity (Research Diagnostic Criteria or Newcastle), dexamethasone suppression test result, drug-free interval, family history of depression, depressive psychosis, suicidal ideation, and past history of suicide attempts were not significantly related to Bmax. Paired comparisons revealed no significant effect on Bmax of 6 weeks' treatment with imipramine, maprotiline, or BRL 14342 or of a course of electroconvulsive therapy.

We have investigated the biochemical basis for the hypersensitivity to intercalating agents and epipodophyllotoxins of a Chinese hamster cell mutant, ADR-1. More topoisomerase II-induced DNA strand breaks are accumulated by ADR-1 than by parental CHO-K1 cells following exposure to the intercalating agent amsacrine. Levels of induced DNA strand breaks correlate with cell killing. Topoisomerase II activity is elevated in ADR-1 cells as a consequence of an increased cellular level of topoisomerase II protein. We have studied the phenotype of cell hybrids generated by fusing parental and mutant cells. The hybrid ADR-1/CHO-K1 exhibits normal levels of resistance to amsacrine and expresses the lower, parental level of topoisomerase II. These results provide additional evidence that topoisomerase II mediates the cytotoxic action of intercalating agents and epipodophyllotoxins and suggest that the intracellular level of topoisomerase II is an important determinant of cellular sensitivity to these drugs. This has implications for antitumor therapy. ADR-1 cells provide a model system for studying the effects of topoisomerase II overproduction on cell proliferation and chromosome organization.

We report the primary structures of two mRNA species (GH1 and GH2), each predicted from the cloned cDNA and genomic gene sequences, that encode growth hormone in rainbow trout (Salmo gairdneri). Both GH1 and GH2 mRNA contain open reading frames comprising 630 nucleotides and encode 210 amino acid residues, of which 11 are variant. The translated regions of mRNA are flanked by a short 5'-untranslated sequence, which is highly conserved, and a relatively long 3'-untranslated sequence, which is highly divergent. The differences at the 3'-untranslated regions suggest that the GH1 and GH2 mRNA originate from different loci. RNA blot analysis of trout pituitary RNA using an oligonucleotide probe specific for the GH2 sequence indicates that the cloned gene is expressed. The GH1 and GH2 mRNA likely are transcribed from two distinct loci, which were duplicated during tetraploidization of the salmonid genome between 50 and 100 million years ago.

The purpose of this investigation was to determine the effect of speakers' attempts to disguise their voices on listeners' accuracy in judgments of height and weight. A total of six sentences were recorded by 26 speakers, 13 females and 13 males, under five conditions: in a normal manner (control condition) and in a manner in which they attempted to sound much taller and much shorter, as well as much heavier and much lighter than they actually were. Five master tapes were constructed, a control tape and four disguise tapes. Each tape contained a total of 156 sentences arranged in random order. A total of 40 judges, 20 in the height-estimation experiment and 20 in the weight-estimation experiment, participated in three sessions, one for each of the three master tapes (one control and two disguise tapes) in each experiment. They were asked to judge the height and weight of the speaker of each sentence and, using a seven-point confidence rating scale, to indicate the over-all confidence in their judgments at the end of each session. Although a majority of speakers yielded height and weight estimates consistent with the intended disguise conditions, the differences in listeners' estimates among all conditions were relatively small. Moreover, differences between speakers' actual heights and weights and listeners' height and weight estimates in the normal (control) condition were also relatively small. Implications of these findings and suggestions for future research are discussed.

[3H]Yohimbine binding to platelet alpha 2-adrenoceptors was studied in depressed patients and healthy volunteers. Where possible platelet binding measurement was repeated in depressed patients following treatment. Bmax of [3H]yohimbine binding did not differ significantly between depressed patients and control subjects and did not change with treatment in depressed patients. KD was significantly lower in female depressed patients, particularly in those who were post-menopausal. Multivariate analysis showed significant effects on KD of depression, season of testing and assay protein concentration.

We have isolated and sequenced a clone from a rainbow trout (Salmo gairdneri) genomic library that carries a gene encoding a fish growth hormone (GH). This gene spans a region of approximately equal to 4 kilobases, nearly twice that of mammalian GH genes. The trout GH gene is comprised of six exons, in contrast with five exons in mammals. The additional intron in the fish gene interrupts translated regions that are analogous to the last exon of its mammalian counterpart. In addition, the alleged internally repeating sequence in mammalian GH, prolactin (Prl), or placental lactogen (PL) is not observed in the predicted polypeptide sequence of fish GH. Direct repeats that flank exons I, III, and V of the mammalian GH, Prl, and PL genes are absent in the fish GH gene. These findings indicate that the rainbow trout GH gene structure does not support the current hypothesis that internally repeated regions in GH, Prl, and PL arose from a small primordial gene.

The purpose of this work was to examine the number and function of alpha 2-adrenoceptors and the number of serotonin uptake sites in depressed patients and controls. Platelet alpha 2-adrenoceptors and platelet serotonin uptake sites were labelled with [3H]yohimbine and [3H]imipramine respectively. Central alpha 2-adrenoceptor function was assessed by growth hormone and other responses to challenge with the alpha 2-agonist clonidine. No overall difference in the binding parameters was observed between the control and depressed groups, but the results highlight the importance of drug-free interval, menopausal status and membrane protein concentration within the binding assays in the interpretation of such studies. The growth hormone response to clonidine tended to be blunted in depressed females and was significantly blunted in the subgroup of depressives who failed to suppress plasma cortisol concentrations in response to dexamethasone. Depressed subjects also showed a smaller decrease in diastolic blood pressure and a smaller increase in sedation than control subjects.

Blood platelet receptors are widely used as peripheral models of central nervous system receptors, particularly in attempts to understand the biological basis of a number of neurological and psychiatric disorders. It is important to differentiate factors other than the primary disease process which may influence platelet receptors. One such potential factor is the menstrual cycle. In this study we have determined platelet high-affinity alpha 2-adrenoceptor binding, using the agonist ligand 3H-UK-14,304 and platelet aggregatory responses to adrenaline in 14 healthy young women, sampled on four occasions at weekly intervals. Our results indicate that, within the limits of individual variation, neither the KD or Bmax of high-affinity 3H-UK-14,304 binding or the aggregatory responses to adrenaline differed significantly between various stages of the menstrual cycle.

Increased numbers of platelet high affinity alpha 2-adrenoceptors binding sites have been reported in depressed patients using the agonist radioligand [3H]clonidine, whereas no differences from controls have been found using antagonist radioligands. We have measured platelet high affinity alpha 2-adrenoceptors in 13 depressed patients and 14 well-matched controls using a new selective agonist radioligand, [3H]UK-14,304. Unlike previous studies using [3H]clonidine, we find no differences in Bmax or KD of the high affinity alpha 2-adrenoceptor binding sites between the 2 groups.

We have isolated two Chinese hamster ovary cell lines, designated ADR-4 and ADR-5, which exhibit hypersensitivity to intercalating agents and epipodophyllotoxins. These drugs are thought to exert their cytotoxicity via an interaction with the enzyme topoisomerase II. However, there is no apparent change in the level or catalytic activity of topoisomerase II in the mutant cells. Drug sensitivity does not appear to be due to increased drug transport because accumulation of radiolabeled actinomycin D is similar in mutant and wild-type cells. Both mutant cell lines show enhanced resistance to hydrogen peroxide and to organic peroxides. ADR-4 cells show a degree of temperature sensitivity. ADR-5 cells show mild sensitivity to UV irradiation. Neither cell line shows significant sensitivity to mono- or bifunctional alkylating agents, ionizing radiation, or bleomycin. Cell fusion studies indicate that the phenotype of each mutant cell line is recessive and that the mutants represent two different genetic complementation groups. These studies also indicate that ADR-4 and ADR-5 Adriamycin-sensitive mutant, ADR-1. These results indicate that sensitivity to topoisomerase II inhibitors can result from abnormalities in several genes. These drug-sensitive mutants may be useful for studying the mechanisms of cell killing by topoisomerase II inhibitors, free radicals, and heat.