Showing papers by "St. Jude Children's Research Hospital published in 1987"

Insulin-like growth factor II receptor as a multifunctional binding protein.

Abstract: The primary structure of human insulin-like growth factor II receptor, predicted from the complementary DNA sequence, reveals a transmembrane receptor molecule with a large extracellular domain made up of fifteen repeat sequences and a small region homologous to the collagen-binding domain of fibronectin. The structural and biochemical features of the IGF-II receptor appear identical to those of the cation-independent mannose-6-phosphate receptor.

Transforming potential of the c-fms proto-oncogene (CSF-1 receptor)

Abstract: The c-fms proto-oncogene encodes a transmembrane glycoprotein that is probably identical to the receptor for the macrophage colony stimulating factor, CSF-11. Forty C-terminal amino acids of the normal receptor are replaced by 11 unrelated residues in the feline v-fms oncogene product2, deleting a C-terminal tyrosine residue (Tyr969) whose phosphorylation might negatively regulate the receptor kinase activity3–5. We show that the human c-fms gene stimulates growth of mouse NIH 3T3 cells in agar in response to human recombinant CSF-1, indicating that receptor transduction is sufficient to induce a CSF-1 responsive phenotype. Although cells transfected with c-fms genes containing either Tyr969 or Phe969 were not transformed, cotransfection of these genes with CSF-1 complementary DNA induced transformation, with c-fms(Phe969) showing significantly more activity than c-fms(Tyr969). In the absence of CSF-1, chimaeric v-fms/c-fms genes encoding the wild-type c-fms C terminus were poorly transforming, whereas chimaeras bearing Phe969 were as transforming as v-fms. Thus, the Phe969 mutation, although not in itself sufficient to induce transformation, activates the oncogenic potential of c-fms in association with an endogenous ligand or in conjunction with mutations elsewhere in the c-fms gene that confer ligand-independent signals for growth.

Varicella in children with cancer: impact of antiviral therapy and prophylaxis.

Abstract: To estimate the impact of antiviral therapy and prophylaxis on the natural course of the infection, 288 cases of varicella in children with cancer were reviewed. Among 127 patients with untreated infections, the overall mortality rate was 7%. Varicella-zoster virus pneumonitis developed in 28% of the untreated patients and was associated with a 25% mortality rate. Pneumonitis was much more likely to develop in patients with acute leukemia than in those with other malignancies (32% v 19%). Similarly, deaths due to pneumonitis were restricted to patients with acute leukemia. Lymphopenia (absolute lymphocyte count less than 500/microL) was significantly associated with varicella-zoster virus pneumonitis and a higher fatality rate among patients with this complication. Both acyclovir and adenine arabinoside, administered to 18 and 28 patients, respectively, stopped the progression of skin lesions; however, pneumonitis developed in none of the acyclovir recipients after two days of treatment, compared with 29% of the adenine arabinoside recipients (P = .03). Passive immunization in 45 children who subsequently had varicella was associated with an 11% incidence of varicella-zoster virus pneumonitis. Despite passive immunization of approximately 150 children, the attack rate of varicella at our institution remains unchanged. Results of this study demonstrate the efficacy of antiviral therapy and passive immunization in patients with childhood cancer and varicella, but prevention of the infection will require a universal vaccine.

Pharmacological, molecular, and cytogenetic analysis of "atypical" multidrug-resistant human leukemic cells.

Abstract: We previously described the cross-resistance patterns and cellular pharmacology of a human leukemic cell line, CEM/VM-1, selected for resistance to the epipodophyllotoxin teniposide (M. K. Danks et al. , Cancer Res., 47: 1297–1301, 1987). Compared to CEM/VLB 100 , which is a well characterized “classic” multidrug-resistant (MDR) cell line, the CEM/VM-1 cells display “atypical” multidrug resistance (at-MDR) in that they are cross-resistant to a wide variety of natural product antitumor drugs, except the Vinca alkaloids, and they are not impaired in their ability to accumulate radiolabeled epipodophyllotoxin. We have extended our characterization of this at-MDR cell line in the present study. In comparison to CEM/VLB 100 cells, we found that CEM/VM-1 cells are not cross-resistant to either actinomycin D or colchicine. Verapamil and chloroquine, which enhance the cytotoxicity of vinblastine in CEM/VLB 100 cells, had little or no ability to do so in the CEM/VM-1 cells. Membrane vesicles of the two resistant sublines were examined for overexpression of the MDR-associated plasma membrane protein (P-glycoprotein, M r 170,000 protein, or 180,000 glycoprotein) by photoaffinity labeling with the vinblastine analogue N -( p -azido[3- 125 I]salicyl)- N′ -β-aminoethylvindesine. We were unable to visualize the MDR-associated protein in the CEM/VM-1 membranes with this photoaffinity probe under conditions in which the P-glycoprotein was readily seen in the membranes of CEM/VLB 100 cells. Furthermore, no hybridization of the pMDR1 complementary DNA was seen in slot-blot analyses of the RNA from at-MDR cells, indicating that the mdr gene coding for P-glycoprotein is not overexpressed as is the case in the classic MDR cells. However, cytogenetic analysis indicated that the CEM/VM-1 cells contained an abnormally banded region on chromosome 13q, suggesting that a gene other than mdr may be amplified in these cells. Thus, despite the two cell lines having approximately equal degrees of resistance to epipodophyllotoxins, our data indicate that the mechanism(s) responsible for at-MDR is different from that for classic, P-glycoprotein-associated MDR.

In situ management of confirmed central venous catheter-related bacteremia.

Abstract: Thirty-one patients with suspected central venous catheter-related bacteremia were evaluated with comparative quantitative cultures of central venous and peripheral blood specimens. Using criteria developed from studies in bacteremic animals, 19 patients were confirmed to have catheter-related bacteremia. Antibiotic therapy was administered through the catheter (in situ therapy) in 17 of those patients to evaluate the feasibility of treating patients with true central venous catheter-related bacteremias without catheter removal. Bacteremia was successfully eradicated in 11 of 17 patients (65%), allowing 7 patients to retain their catheter a median of 157 days. This study validates the use of comparative quantitative blood cultures in the diagnosis of catheter-related bacteremia and indicates that in situ therapy is a rational alternative to catheter removal in patients with catheter-related bacteremia.

Thoracotomy for pulmonary metastatic osteosarcoma. An analysis of prognostic indicators of survival.

Abstract: Removal of pulmonary metastases of osteosarcoma by thoracotomy is an accepted treatment; however, few investigators have analyzed the value of various prognostic factors in estimating survival. A review of all patients undergoing thoracotomy for recurrent osteosarcoma with pulmonary metastases treated at St. Jude Children's Research Hospital is reported. Since 1968, two thirds (39/59) of all patients who developed pulmonary metastases have had a total of 66 thoracotomies. Nine patients are alive with no evidence of disease, and six additional patients are alive with disease. Analyzed in 39 evaluable patients, the prognostic factors that correlate with survival by univariate analysis are: sex, number of nodules detected radiographically and resected, completeness of resection, and tumor location (bilateral versus unilateral). By Cox regression analysis, only sex and the number of nodules detected either radiographically or during surgery, and resected, had statistically significant correlation with survival. Thoracotomy is curative for some patients with pulmonary metastatic osteosarcoma and Prognostic factors predictive for survival are defined.

Induction of Prostaglandin Synthesis as the Mechanism Responsible for the Chills and Fever Produced by Infusing Amphotericin B

Abstract: Amphotericin B produces chills and fever in a significant proportion of patients who receive this drug. The mechanism for this adverse effect is unknown. Amphotericin B suspension at a concentration of 1.0 microgram/ml was demonstrated to be a potent inducer of prostaglandin E2 synthesis by human and murine mononuclear cells in vitro. A double-blind, placebo-controlled clinical trial demonstrated that ibuprofen (10 mg/kg), a potent inhibitor of prostaglandin synthesis, administered 30 min before amphotericin B administration reduced the incidence of chilling from 87% to 49% (P = .01); the incidence of chilling reactions considered severe was reduced from 69% to 15% (P = .008). We postulate that the chills and fever produced by an infusion of amphotericin B are mediated through prostaglandin E2 synthesis. Ibuprofen is therapeutically useful in ameliorating the chills and fever caused by amphotericin B.

Hepatic undifferentiated (embryonal) sarcoma and rhabdomyosarcoma in children. Results of therapy.

Abstract: From July 1972 through September 1984, 8 of 44 children diagnosed as having primary malignant hepatic tumors, who were treated at St. Jude Children's Research Hospital, had undifferentiated (embryonal) sarcoma (five patients) or rhabdomyosarcoma (three patients). The natural history and response to multimodal therapy of these rare tumors are described. The pathologic material was reviewed and evidence for the differentiating potential of undifferentiated (embryonal) sarcoma is presented. At diagnosis, disease was restricted to the right lobe of the liver in three patients, was bilobar in four patients, and extended from the left lobe into the diaphragm in one patient. Lung metastases were present in two patients at diagnosis. All three patients with rhabdomyosarcoma had intrahepatic lesions without involvement of the biliary tree. Survival ranged from 6 to 73 months from diagnosis (median, 19.5 months); two patients are surviving disease-free for 55+ and 73+ months, and one patient recently underwent resection of a recurrent pulmonary nodule 22 months from initial diagnosis. Three patients died of progressive intrahepatic and extrahepatic abdominal tumors, and two patients, who died of progressive pulmonary tumor, also had bone or brain metastasis but no recurrence of intra-abdominal tumor. Six patients had objective evidence of response to chemotherapy. The authors suggest an aggressive multimodal approach to the treatment of these rare tumors in children.

Pharmacokinetics of anticancer drugs in children

Abstract: Interpatient pharmacokinetic variability normally observed in adults is often of even greater magnitude in paediatric patients because of age-related maturation of physiological processes responsible for drug disposition. Several antineoplastic agents have shown age-related changes, including alterations in volume of distribution, hepatic (doxorubicin, cyclophosphamide), and renal (bleomycin, methotrexate) clearances. These differences in pharmacokinetics as a function of age alter systemic exposure to chemotherapy, and may alter the efficacy and toxicity profile for standard doses of antineoplastic drugs. The relationship of systemic exposure to toxicity has been most clearly defined for methotrexate. Clinical monitoring of methotrexate serum concentrations, and adjustment of folinic acid dosages and duration of rescue based on methotrexate disposition is now routine. More recently, pharmacodynamic data have been published for high-dose methotrexate, epipodophyllotoxins, cisplatin, and cytarabine (cytosine arabinoside), indicating a relation between drug disposition and toxicity or efficacy. Collectively, these data suggest that the pharmacokinetics of many anticancer drugs in children is different from adults, and that variability in drug disposition may have an important influence on toxicity or efficacy.

Mutagenic activity of chloramines.

Abstract: Mutagenesis by chloramines and hypochlorous acid (HOCl) was studied to determine whether these agents could contribute to the mutagenic and potentially carcinogenic activity of stimulated leukocytes and whether environmental exposure to these agents is a cause for concern. Mutagenic activity was measured using the S. typhimurium TA97a, TA100 and TA102 tester strains. Because chloramines and HOCl are bactericidal, react rapidly with cell components, and can destroy the histidine and biotin required for the mutagenesis assay, activity can't be compared directly with that of less toxic or reactive agents. Nevertheless, chloramines were mutagenic when tested under appropriate conditions. TA100 was the most sensitive strain, and the most active mutagens were lipophilic dichloramines (RNCl2) including derivatives of histamine, ethanolamine and putrescine. Lipophilic monochloramines (RNHCl) such as histamine-monochloramine and NH2Cl were less active. Hydrophilic chloramines such as taurine-chloramines had low activity, and HOCl was inactive. The metabolic state of the bacteria was critical. Chloramines were mutagenic when added to bacteria with glucose at 37 degrees C, but killing predominated when chloramines were added at 4 degrees C or 25 degrees C, or at 37 degrees C without glucose. Production of chloramines and HOCl by leukocytes in vivo could contribute to the association of chronic inflammation and cancer as a result of: (1) the entry of membrane-permeable chloramines into normal cells followed by attack on intracellular components including DNA, and (2) the production of secondary mutagens such as compounds with carbonyl groups or carbon-chlorine bonds. On the other hand, chlorination of water supplies is perhaps more likely to destroy than create mutagens, and chloramines from the environment are unlikely to penetrate the skin and mucous membranes.

Polymyxin B Moderates Acidosis and Hypotension in Established, Experimental Gram-Negative Septicemia

Abstract: Polymyxin B (PMB), an antibiotic, and sodium deoxycholate (NaD), a bile salt, are surface-active agents. Each protected mice against an otherwise lethal challenge with purified endotoxin (P less than .001). To determine if either of these agents was effective in treating established, overwhelming gram-negative septicemia, we infected rabbits by intraperitoneal injection of Escherichia coli K1. Animals were treated with moxalactam 1 hr after infection, then randomly assigned to groups receiving either saline, PMB, or NaD. Serial samples of blood were assayed for bacterial concentration, levels of plasma endotoxin, arterial blood gases, and complete blood cell counts. Physiologic functions were monitored continuously. Although levels of bacteremia and endotoxemia were similar in all three groups, rabbits receiving PMB had significantly higher mean arterial blood pressure, blood pH, and bicarbonate concentrations than did control rabbits (P less than .05). Rabbits receiving NaD fared no better than controls. In this model, PMB moderates some of the deleterious effects of established, overwhelming gram-negative bacterial sepsis.