Biomedical subjects

A Cnaan

Publications and source records attributed to A Cnaan.

At least 19 recordsLinked to original sources

PubMed2000

Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma.

Neuroblastoma (NB) is a common pediatric tumor that exhibits a wide range of biological and clinical heterogeneity. EPH (erythropoietin-producing hepatoma amplified sequence) family receptor tyrosine kinases and ligand ephrins play pivotal roles in neural and cardiovascular development. High-level expression of transcripts encoding EPHB6 receptors (EPHB6) and its ligands ephrin-B2 and ephrin-B3 (EFNB2, EFNB3) is associated with low-stage NB (stages 1, 2, and 4S) and high TrkA expression. In this study, we showed that EFNB2 and TrkA expressions were associated with both tumor stage and age, whereas EPHB6 and EFNB3 expressions were solely associated with tumor stage, suggesting that these genes were expressed in distinct subsets of NB. Kaplan-Meier and Cox regression analyses revealed that high-level expression of EPHB6, EFNB2, and EFNB3 predicted favorable NB outcome (P<0.005), and their expression combined with TrkA expression predicted the disease outcome more accurately than each variable alone (P<0.00005). Interestingly, if any one of the four genes (EPHB6, EFNB2, EFNB3, or TrkA) was expressed at high levels in NB, the patient survival was excellent (>90%). To address whether a good disease outcome of NB was a consequence of high-level expression of a "favorable NB gene," we examined the effect of EPHB6 on NB cell lines. Transfection of EPHB6 cDNA into IMR5 and SY5Y expressing little endogenous EPHB6 resulted in inhibition of their clonogenicity in culture. Furthermore, transfection of EPHB6 suppressed the tumorigenicity of SY5Y in a mouse xenograft model, demonstrating that high-level expressions of favorable NB genes, such as EPHB6, can in fact suppress malignant phenotype of unfavorable NB.

Animals↗

PubMed2000

Baseline prediction of 7-month cocaine abstinence for cocaine dependence patients.

A broad range of baseline subject variables was evaluated to identify predictors of 7-month cocaine use for 160 lower socioeconomic cocaine dependent male veteran patients participating in either an intensive 1-month day hospital (DH; n=90) or a 1-month inpatient (INP; n=70) treatment program. The baseline measures included sociodemographic variables, the seven Addiction Severity Index composite scores, cocaine urine toxicology, craving, the SCL-90 total score, and lifetime psychiatric diagnoses. Since a proportion of subjects who reported no use at follow-up had positive urines, both liberal and conservative data estimation strategies were employed for subjects without urine toxicology data at follow-up who had reported no use (21% of subjects). Analyses were done separately for the DH and INP subjects. Under the conservative definition of cocaine abstinence/use, univariate correlations of predictor variables with 7-month cocaine use revealed no statistically significant relationships. Under the liberal definition of cocaine abstinence/use, only one variable, greater severity of alcohol problems at intake predicted cocaine abstinence at outcome. Because of the inability to predict treatment success, originally planned logistic regression analyses were not undertaken. The findings point to the difficulty of predicting long-term outcomes in cocaine dependent patients based on baseline information and to the importance of obtaining objective data on cocaine use.

Adult↗

PubMed2000

Longitudinal evaluation of cardiopulmonary performance during exercise after bone marrow transplantation in children.

OBJECTIVE: Abnormalities in cardiopulmonary performance during exercise have been reported in children after bone marrow transplantation (BMT). We sought to study changes in exercise performance over time in pediatric BMT survivors. STUDY DESIGN: We retrospectively reviewed the results of serial cardiopulmonary exercise tests performed by patients who had undergone BMT at our institution. Four measurements of cardiopulmonary function are reported: maximum cardiac index (MCI), maximal oxygen consumption (Max VO(2)), oxygen consumption at ventilatory threshold (VO(2) at VT), and maximum work (Max Work) performed. A linear mixed-effects model was fitted to assess changes in these parameters over time. RESULTS: Thirty-three patients performed 96 cardiopulmonary exercise tests. MCI and VO(2) at VT were depressed at initial testing and did not change over time. Max VO(2) increased by 4% per year to 69% predicted, and Max Work increased to 77% predicted at 6 years after BMT. CONCLUSIONS: In spite of an impaired cardiovascular response to exercise as indicated by the persistently low MCI, aerobic and physical working capacity increase. Improved Max VO(2) suggests that oxygen extraction at the musculoskeletal level becomes more efficient with recovery from BMT. This may represent a compensatory response to an impaired ability to increase cardiac output.

Adolescent↗

PubMed2000

TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors.

PURPOSE: To identify biologic prognostic factors in childhood primitive neuroectodermal tumors (PNET), including medulloblastoma, that accurately define patient groups with sufficiently good prognosis to permit a reduction in treatment intensity. PATIENTS AND METHODS: We determined expression levels of the neurotrophin receptor TrkC mRNA in formalin-fixed tumor samples from 87 well characterized PNET patients using in situ hybridization. Comparison of TrkC mRNA expression levels with clinical and other laboratory variables was performed using univariate and multivariate Cox regression analysis. RESULTS: High TrkC mRNA expression was found to be associated more with higher 5-year cumulative survival rate than was low TrkC mRNA expression (89% v 46%, respectively). When compared with established clinical prognostic factors and laboratory variables of potential prognostic significance, TrkC mRNA expression, by univariate analysis, was found to be the single most powerful predictor of outcome (hazards ratio, 4.81; P <.00005), exceeding all clinical prognostic factors. In multivariate analysis, the hazards ratio remained significant (P <.00005). CONCLUSION: High TrkC mRNA expression in PNET is a powerful independent predictor of favorable clinical outcome. Assessment of TrkC mRNA levels may aid in treatment planning for patients with PNETs and should be incorporated prospectively into PNET clinical trials.

Adolescent↗

PubMed2000

Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype.

BACKGROUND: Characteristic behaviors of some alcohol-dependent individuals, e.g., binge drinking, comorbid psychopathology, and some types of alcohol-related problems, have been linked to abnormalities in serotonergic neurotransmission. However, studies that have evaluated serotonergic pharmacotherapy for reducing drinking have yielded conflicting results. One explanation for these findings is a general failure to distinguish alcohol subgroups that may be differentiated on the basis of serotonergic abnormalities. However, in 1996, Kranzler and colleagues reported that Type B alcoholics, who are characterized by high levels of premorbid vulnerability, alcohol dependence severity, and comorbid psychopathology, showed less favorable drinking outcomes in response to treatment with fluoxetine, a serotonin reuptake inhibitor, than with placebo. This medication effect was not seen in Type A alcoholics, i.e., those with lower risk/severity of alcoholism and psychopathology. The aim of the present study was to explore the validity of differential responding by alcohol-dependent subtypes using the serotonin reuptake inhibitor, sertraline. METHODS: A k-means clustering procedure was applied to a sample of alcohol-dependent subjects enrolled in a 14-week, placebo-controlled trial of 200 mg/day of sertraline, classifying them into lower-risk/severity (Type A: n = 55) and higher-risk/severity (Type B: n = 45) subgroups. RESULTS: A significant interaction between alcoholic subtype and medication condition was found, confirming the findings of Kranzler and colleagues that alcoholic subtypes responded differentially to serotonergic medication. Somewhat at variance with their results, however, the present study showed that the lower risk/severity (Type A) subjects had more favorable outcomes when treated with sertraline compared to placebo. CONCLUSIONS: Alcoholic subtypes differentially responded to sertraline when used as a treatment to reduce alcohol drinking, with one subtype having more favorable outcomes. Subtyping alcoholics may help to resolve conflicting findings in the literature on serotonergic treatment of alcohol dependence.

Adolescent↗

PubMed1999

Cotinine replacement levels for a 21 mg/day transdermal nicotine patch in an outpatient treatment setting.

This study examined plasma cotinine replacement levels of 56 outpatient smokers administered a 21 mg/day transdermal nicotine patch (Nicoderm CQ ). The percentage of cotinine replacement ranged from 35 to 232% (mean 107%; median 90.5%). Four subject variables were found to be significantly correlated with percentage of cotinine replacement-baseline cotinine level, prior quit attempts, gender, and the Fagerström Tolerance Questionnaire score. A two-variable model consisting of baseline cotinine level and gender provided the most powerful predictor combination. The percentage of cotinine replacement was not predictive of post-treatment smoking. The relatively high levels of cotinine replacement obtained using the Nicoderm CQ 21 mg/day patch suggest cautious use of higher dose treatment with this particular patch.

Administration, Cutaneous↗

PubMed1999

Methadone-maintenance outcomes for Hispanic and African-American men and women.

Six-month methadone-maintenance response and outcome were examined for African-American and Hispanic men and women in a large urban sample. A consistent pattern of improvement was indicated for both races and genders on the addiction severity index (ASI). There were virtually no statistically significant differences in ASI outcomes between Hispanics and African-Americans and men and women using conventional analysis of variance (ANOVA) procedures. Results from an additional equivalence analysis, however, indicated that baseline to 6-month changes for the different groups were generally not similar enough to consider them equivalent. Urine toxicologies obtained during the 6-month treatment period were also not statistically equivalent by race and gender. Evaluating outcomes by gender and race are discussed, as are the implications of using equivalence tests when examining group differences.

Black or African American↗

PubMed1999

Nicodermal patch adherence and its correlates.

The patch adherence behavior of 101 smokers receiving 8 weeks of the nicodermal patch was examined while undergoing one of three levels of adjunctive psychosocial treatment. Additionally, regression analyses were undertaken to: (1) identify subject variables predictive of patch adherence and (2) to determine the predictive validity of patch treatment dropout, smoking and patch adherence during patch treatment to smoking 9 and 26 weeks post-treatment entry. Fifty-five percent of the patients wore the patch as prescribed for at least 50 of 56 treatment days. A multiple regression model including the Fagerström severity of dependence score, psychosocial treatment group, and the URICA commitment score predicted 18% of the variance in days of patch use. All treatment dropouts were found to be smoking at followup. Although both smoking and low patch compliance during treatment were significant predictors subjects of week 9 and 26 smoking for the remaining subjects, at the individual variable level of analysis, only smoking during treatment predicted week 9 and 26 outcomes in a two-variable predictor model.

Administration, Cutaneous↗

PubMed1999

Multiple courses of antenatal corticosteroids and outcome of premature neonates. North American Thyrotropin-Releasing Hormone Study Group.

OBJECTIVES: We sought to examine outcome for premature neonates after multiple courses of antenatal corticosteroids compared with a single course. STUDY DESIGN: We performed a post hoc nonrandomized analysis on 710 neonates of 25-32 weeks' gestation who were born to mothers enrolled in the North American Thyrotropin-Releasing Hormone Trial and who received 1, 2, or >/=3 courses of antenatal corticosteroids. RESULTS: There was no detectable clinical difference in incidence of respiratory distress syndrome, chronic lung disease, and intraventricular hemorrhage related to courses of antenatal corticosteroids, and outcome was similar for infants delivered at 7-13 days compared with those delivered at 1-6 days after receiving antenatal corticosteroids. Compared with those who received a single course, neonates who received >/=2 courses had lower birth weights (-39 g, P =.02), and those receiving >/=3 courses had increased risk of death (adjusted odds ratio, 2.8; 95% confidence interval, 1.3-5.9; P =.01) and lower levels of plasma cortisol at age 2 hours. CONCLUSION: In this retrospective analysis multiple courses of antenatal corticosteroids did not improve outcome and were associated with increased mortality, decreased fetal growth, and prolonged adrenal suppression.

Adrenal Cortex Hormones↗

PubMed1999

Looking beyond the physical injury: posttraumatic stress disorder in children and parents after pediatric traffic injury.

BACKGROUND: Traffic crashes are the leading health threat to children in the United States, resulting in nearly 1 million injuries annually. The psychological consequences of these injuries are primarily unknown. The aims of this study were to estimate the prevalence of posttraumatic stress disorder (PTSD) in traffic-injured children and their parents and to identify risk factors for PTSD development. METHODS: A prospective cohort study of traffic-injured children between 3 and 18 years of age was conducted at a level 1 Pediatric Trauma Center. The children were enrolled as part of an ongoing surveillance system of traffic-related injuries. Presence and severity of PTSD were determined in the children and their parents through a validated diagnostic questionnaire 7 to 12 months after child injury. RESULTS: Twenty-five percent of the children and 15% of the parents suffered diagnostic PTSD, but only 46% of the parents of affected children sought help of any form (including from friends) for their child and only 20% of affected parents sought help for themselves. Child PTSD was associated with older child age and parent PTSD. Parent PTSD was associated with younger child age, child PTSD, and parent witnessing the event. Injury severity was not predictive of PTSD. CONCLUSIONS: PTSD in children and their parents is a common, yet overlooked, consequence of pediatric traffic-related injury with prevalence rates similar to those found in children exposed to violence. Physicians managing the pediatric trauma patient, regardless of injury severity or whether the injury was intentional, should screen for PTSD and refer for treatment where appropriate.

Accidents, Traffic↗

PubMed1999

High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas.

Neuroblastoma (NB) is a common pediatric tumor of neural crest origin that is biologically and clinically heterogeneous. EPH family receptor tyrosine kinases and ephrin ligands play fundamental roles in neurodevelopmental processes. Recently, we found that NB cell lines expressed several EPHB and EFNB transcripts, which encode EPHB subgroup receptors and ephrin-B subgroup ligands, respectively. To explore the role of EPHB receptors and ephrin-B ligands in the biology of NB, we examined the expression of EPHB and EFNB transcripts in 47 primary NB specimens. Multiple EPHB and EFNB transcripts were expressed in all of the NB tumors examined, suggesting the involvement of these transcripts in modulating the biological behavior of NB. Higher levels of EPHB6, EFNB2, and EFNB3 expression were found in low-stage tumors (stage 1, 2, and 4S) than in advanced-stage tumors (stage 3 and 4; P = 0.0013, P = 0.0048, and P = 0.027, respectively). Expression of TrkA, a well-established prognostic marker of favorable NB, was positively correlated with EPHB6, EFNB2, and EFNB3 expression (P < 0.0001, P = 0.0019, and P = 0.0001, respectively). MYCN-amplified tumors expressed lower levels of EPHB6, EFNB2, EFNB3, and TrkA transcripts compared to nonamplified tumors (P = 0.0006, P = 0.0023, P = 0.0048, and P = 0.0001, respectively). These data suggest that high-level expression of EPHB6, EFNB2, and EFNB3 is associated with favorable NB and that low-level expression of EPHB6, EFNB2, and EFNB3 correlates with aggressive MYCN-amplified NB. Thus, EPHB6, EFNB2, and EFNB3 may have biological relevance in NB. Further investigation on the biology of these genes may help provide insight into the treatment of NB.

Ephrin-B2↗

PubMed1998

Salvage therapy after postoperative chemotherapy for primary brain tumors in infants and very young children.

BACKGROUND: A trend toward the use of prolonged postoperative chemotherapy, with radiotherapy deferred until relapse, has emerged for very young children with malignant brain tumors. This study was undertaken to determine the failure patterns among infants who receive such treatment and to evaluate their responses to first salvage therapy, particularly radiotherapy, after postoperative chemotherapy. METHODS: A retrospective cohort was assembled, which comprised all children younger than 36 months with biopsy-proven malignant brain tumors diagnosed during the years 1987-1993 at 3 pediatric oncology referral centers. Fifty-eight children were treated with postoperative chemotherapy without irradiation, 40 of whom experienced relapse of their malignancy. These patients' charts were reviewed for failure patterns. Thirty-five of these children received salvage therapy. Statistical and survival analysis with the Cox proportional hazards regression model was performed. RESULTS: Among the 40 children who experienced relapse, 30 of 31 (97%) with solitary disease at initial diagnosis relapsed at the primary site of disease. Thirty-seven of 39 infants (95%) developed relapse that included their primary site of disease. Sixty percent of relapses were asymptomatic and were detected by magnetic resonance imaging (MRI) surveillance rather than by clinical examination. Two-year progression free survival (PFS) after relapse for infants who received salvage therapy was 29% (standard error [SE] = 8%). For infants who received radiotherapy alone, the 2-year PFS was 21% (SE = 9%). PFS did not differ according to whether relapses were detected clinically or radiographically or treated by radiotherapy, chemotherapy, surgery, or multimodal therapy. CONCLUSIONS: Relapse of brain tumors in infants after prolonged postoperative chemotherapy is largely a problem of local disease control. Salvage is possible after prolonged postoperative chemotherapy, but it yields few instances of long term, progression free survival. No therapeutic modality is superior for salvage at relapse. A strategy of reserving radiotherapy for the salvage of infants whose brain tumors relapse during postoperative chemotherapy demonstrated only limited effectiveness.

Brain Neoplasms↗

PubMed1998

Identification of a consistent region of allelic loss on 1p32 in meningiomas: correlation with increased morbidity.

Meningioma is a common tumor of the central nervous system. Deletions of the short arm of chromosome 1 (1p) are the second most commonly observed chromosomal abnormality in these tumors. Here, we analyzed tumor and normal DNAs from 157 meningioma patients using PCR-based polymorphic loci. Loss of heterozygosity (LOH) for at least one informative marker on 1p was observed in 54 cases (34%), whereas LOH on 1q occurred in only 9 cases (8%). High-resolution deletion mapping defined a consensus region of deletion flanked distally by D1S2713 and proximally by D1S2134, which spans 1.5 cM within 1p32. LOH in this region has also been observed in several other malignancies, suggesting the presence of a tumor suppressor gene or genes that are important for several types of cancer. Statistical analysis revealed that 1p LOH was associated with chromosome 22 deletions and with abnormalities of the NF2 gene in meningioma. In addition, unlike other clinical and molecular characteristics, only 1p LOH was shown to be significantly associated with recurrence-free survival.

Alleles↗

PubMed1998

Antenatal thyrotropin-releasing hormone to prevent lung disease in preterm infants. North American Thyrotropin-Releasing Hormone Study Group.

BACKGROUND: Pulmonary disease is common in preterm infants, despite antenatal glucocorticoid therapy. The addition of antenatal thyrotropin-releasing hormone therapy has been reported to decrease pulmonary morbidity in these infants. METHODS: We enrolled 996 women at 13 North American centers who were in preterm labor at <30 weeks' gestation in a double-blind, placebo-controlled, randomized trial of antenatal thyrotropin-releasing hormone, given intravenously in four doses of 400 microg each at eight-hour intervals. The primary outcome was chronic lung disease or death of the infant on or before the 28th day after delivery, and secondary outcomes were respiratory distress syndrome and chronic lung disease or death at 36 weeks' postmenstrual age. Complete data were available for 981 women and their 1134 live-born infants. The 769 infants born at < or = 32 weeks' gestation were defined as the group at risk. RESULTS: There were no significant differences between the at-risk treatment and placebo groups in mean (+/-SD) birth weight (1109+/-354 vs. 1097+/-355 g), gestational age (27.9+/-2.1 vs. 27.9+/-2.1 weeks), sex, or race. The frequencies of respiratory distress syndrome (66 percent vs. 65 percent), death at 28 days (11 percent vs. 11 percent), chronic lung disease or death at 28 days (45 percent vs. 42 percent) and at 36 weeks (32 percent vs. 34 percent), and other neonatal complications as well as the severity of lung disease were not significantly different in the at-risk treatment and placebo groups. Similarly, there were no differences in outcome between the treatment and placebo groups for the infants born at >32 weeks' gestation. CONCLUSIONS: In preterm infants at risk for lung disease, antenatal administration of thyrotropin-releasing hormone and glucocorticoid is no more beneficial than glucocorticoid alone.

Adult↗

PubMed1998

Short interpregnancy interval and the risk of disabling cerebral palsy in a low birth weight population.

OBJECTIVE: The objective of this study was to investigate the relation of short interpregnancy interval and cerebral palsy (CP) in a low birth weight population in whom neonatal brain injury was systematically ascertained in the newborn period. STUDY DESIGN: We used data from a prospective cohort study of 1105 infants born < or = 2000 gm, designed to study the cause and consequences of neonatal brain injury. Of the 777 children with data on brain injury and CP, 382 were born to multiparous women, and 375 had information available to calculate interpregnancy interval, defined as the number of days from the end of the last pregnancy to conception of the index pregnancy. RESULTS: In the presence of the strong explanatory power of neonatal brain injury, short interpregnancy interval maintains an independent risk for disabling CP. CONCLUSION: In this cohort of low birth weight infants, short interpregnancy interval appears to represent a significant risk for the development of disabling CP.

Birth Intervals↗

PubMed1998

Bcl-2 oncoprotein positivity and high MIB-1 (Ki-67) proliferative rate are independent predictive markers for recurrence in prostate carcinoma.

Predicting the clinical behavior of prostate carcinoma can be difficult; one approach is to identify molecular prognostic markers. We evaluated proliferative rate (MIB-1 antibody) and expression of bcl-2, p53, and retinoblastoma (pRB) proteins, which have cell cycle-related functions, in 208 consecutive radical prostatectomy specimens. Values were correlated with histopathologic parameters (Gleason tumor score, tumor amount, capsule invasion, and involvement of surgical margins, seminal vesicles, or lymph nodes) and with recurrence-free survival (4-year median follow-up). A high MIB-1 proliferative rate was associated with all of the measured histopathologic parameters, p53 overexpression with tumor amount, and pRB expression with positive lymph nodes. pRB and p53 expression levels were not associated with differences in recurrence-free survival. A high MIB-1 proliferative rate and bcl-2 positivity were associated with increased recurrence, both considered individually, and also independently and additively when examined together and with the most predictive histopathologic factors (Gleason tumor score and seminal vesicle involvement). MIB-1 proliferative rate and bcl-2 positivity may prove to be useful markers for poor prognosis in prostate carcinoma.

Biomarkers, Tumor↗

PubMed1998

A comparison of awake versus paralyzed tracheal intubation for infants with pyloric stenosis.

UNLABELLED: This prospective, nonrandomized, observational study of 76 infants with pyloric stenosis was conducted at an academic children's hospital and compared awake versus paralyzed tracheal intubation in terms of successful first attempt rate, intubation time, heart rate (HR) and arterial hemoglobin oxygen saturation (SpO2) changes, and complications. Three groups were determined by intubation method: awake (A) with an oxygen-insufflating laryngoscope, after rapid-sequence induction (R), or after modified rapid-sequence induction (M) including ventilation through cricoid pressure. Successful first attempt intubation rate was 64% for Group A versus 87% for paralyzed Groups R and M (P = 0.028). Median intubation time was 63 s in Group A versus 34 s in Groups R and M (P = 0.004). Transient, mild decreases in mean HR and SpO2 and incidences of significant bradycardia and decreased SpO2 did not vary by group. Complications, including bronchial or esophageal intubation, emesis, and oropharyngeal trauma, were few. Senior anesthesiologists intervened in four tracheal intubations. We advocate anesthetized, paralyzed tracheal intubation because struggling with conscious infants takes longer, often requires multiple attempts, and prevents neither bradycardia nor decreased SpO2. After induction, additional mask ventilation with O2 confers no advantage over immediate tracheal intubation in preserving SpO2. IMPLICATIONS: In our children's hospital, awake tracheal intubation was not superior to anesthetized, paralyzed intubation in maintaining adequate oxygenation and heart rate or in reducing complications, and should be abandoned in favor of the latter technique for routine anesthetic management of otherwise healthy infants with pyloric stenosis.

Anesthesia↗

PubMed1998

Synergistic cytotoxicity of topoisomerase I inhibitors with alkylating agents and etoposide in human brain tumor cell lines.

To evaluate potential synergistic interactions between topoisomerase I (Topo I) inhibitors, i.e. camptothecin (CPT) and topotecan (TPT), and chemotherapeutic agents known to be active in treatment of brain tumors, in vitro studies were conducted with human glioma and medulloblastoma cell lines. Tumor cells were exposed to CPT or TPT alone or in combination with cisplatin, 4-hydroperoxycyclophosphamide (4-HC), BCNU or etoposide (VP-16). Cytotoxicity was assessed by colony formation assays. Drug interactions were evaluated by means of a novel analytical model which permits statistical evaluation over a range of dose combination. Experimental results were corroborated by published models of drug interaction. Our findings indicate that in vitro cytotoxic interactions in brain tumor cells between Topo I inhibitors and alkylating agents or etoposide depend on drug dose, dose schedule and tumor cell line. Treatment of DAOY medulloblastoma cells with CPT and either cisplatin, 4-HC or VP-16 produced significant synergistic cytotoxicity over a wide range of dose combinations. When VP-16 was administered after CPT, synergy was reduced to a narrow range of dose combinations. For U251 glioma cells, incubation with CPT and cisplatin or 4HC also produced synergistic cytotoxicity over a broad range of dose combinations. By contrast, antagonistic interactions were observed after administration of CPT with BCNU or VP-16. Treatment of U251 cells with CPT and cisplatin produced synergistic or antagonistic cytotoxicity depending on the dose combination used. These findings support a role for pharmacokinetic analysis in multiagent phase 11 trials involving Topo I inhibitors and have important implications for clinical trial design strategies.

Antineoplastic Agents↗