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Biomedical subjects

B Storer

Publications and source records attributed to B Storer.

80 records · Page 5Linked to original sources
PubMed1987

Platinum analogue combination chemotherapy: cisplatin and carboplatin--a phase I trial with pharmacokinetic assessment of the effect of cisplatin administration on carboplatin excretion.

Cisplatin (NSC 119875) and carboplatin (NSC 241240) are platinum (II) analogues with very different spectra of toxicity. Cisplatin dose is limited by nausea and vomiting, renal dysfunction, and dose-related peripheral neuropathy, whereas carboplatin is myelosuppressive. There are also clinical and laboratory data that suggest that these drugs may not be completely cross-resistant. Therefore, the following phase I trial of combination therapy with cisplatin and carboplatin was undertaken. Since carboplatin toxicity is enhanced in the presence of renal impairment, carboplatin excretion was also evaluated in selected patients at the maximum tolerated dose. Thirty-three patients received 50 mg/m2 cisplatin and doses of carboplatin between 160 mg/m2 and 400 mg/m2. Sequential 20-minute infusions of carboplatin and then cisplatin were able to be administered at the standard doses of carboplatin (320 and 400 mg/m2) with thrombocytopenia to the degree expected if carboplatin alone had been given. However, 280 mg/m2 carboplatin followed by 25 mg/m2 cisplatin/d X 3 caused unexpectedly severe thrombocytopenia in seven of eight patients (median platelet nadir 45,000/microL; range, 12 to 321,000/microL; nadir was less than 90,000 in seven of eight patients). In three patients treated with 280 mg/m2 carboplatin plus 25 mg/m2/d X 3 cisplatin, pharmacokinetics of carboplatin were compared during consecutive monthly cycles without and with cisplatin. Modestly increased areas under the curve (AUC) for carboplatin (15% and 35%) with cisplatin were seen in the two patients who experienced more pronounced platelet suppression with combination therapy. No other limiting or unusual toxicity was seen with this combination. Responses, primarily in "platinum responsive" tumors, were seen. The combination of cisplatin plus carboplatin is feasible and merits further study.

Anemia↗
PubMed1987

Phase I trial of combinations of recombinant interferons beta(ser) and gamma in patients with advanced malignancy.

Based upon in vitro and in vivo synergistic activity of Type I and Type II interferons (IFNs) in preclinical in vitro and in vivo studies, we initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of combinations of recombinant DNA-produced human IFN-beta ser and IFN-gamma in 27 patients with cancer. Twenty-four patients were treated with a 2-hour infusion of IFN-gamma, followed by a 10-minute iv injection of IFN-beta ser, three times a week. Patients were entered on fixed dose levels of 1 X 10(6), 3 X 10(6), 10 X 10(6), 30 X 10(6), and 100 X 10(6) units of each IFN. In addition, three patients were treated at the highest dose level with a 10-minute iv infusion of IFN-gamma and a 10-minute iv infusion of IFN-beta ser. The maximally tolerated dose when administered by this schedule for greater than or equal to 4 weeks was 30 X 10(6) units of each IFN. Dose-limiting side effects at doses of 100 X 10(6) units of each IFN consisted of fatigue, nausea, vomiting, anorexia, paralytic ileus, and neutropenia. The most common side effects at the three highest dose levels were fever, rigors often requiring parenteral meperidine, and constitutional symptoms. Reversible elevations in SGOT and LDH were also noted. Serum IFN levels were dose related, with peak titers occurring immediately after IFN administration. One patient with a nodular mixed lymphoma had a partial response which has been sustained for over 1 year. We conclude that combinations of IFN-beta ser and IFN-gamma can be safely administered on a chronic basis without enhanced or cumulative toxic effects.

Adolescent↗
PubMed1987

Phase 1 clinical evaluation of recombinant interleukin-2.

The availability of large quantities of pure recombinant IL-2 has permitted clinical studies of its effects in patients with cancer. Based on the rapid half-life (3-5 minutes) and the need for prolonged exposure to IL-2 to maximally stimulate responsive cells we conducted a Phase 1 clinical trial designed to compare the clinical tolerance, immunologic effects and antitumor activity of IL-2 given by CI and daily BI for 7 consecutive days. The MTD of IL-2 based on completion of 7 days of treatment was found to be 3 X 10(6) U/m2/day for BI and 10(6) U/m2/day for CI. These results are approximately equivalent to those reported by others (Lotze, 1985 and Atkins, 1986), provided corrections are made for activity (2.3 Cetus IL-2 units = 1 BRMP IL-2 Unit). Although dose limiting toxicity was observed at the higher doses of IL-2 tested, these doses were tolerated for a shorter period of time (3-4 days) with striking immunologic effects (Sondel et al. 1987). As such, shorter treatment schedules utilizing higher doses of IL-2 warrant further investigation. The toxicity associated with the administration of IL-2 is considerable and clearly dose related. Of particular clinical importance is the fever, hypotension, fluid accumulation and decrease in PS. The etiology of these toxicities appears to be related to the release of endogenous cytokines following activation of the patient's immune system. It is also possible that the in vivo activation by IL-2 of cells mediating NRC may play some role in the toxicity associated with IL-2 (Sondel, 1986). It remains unclear whether immunosuppressive methods such as the use of cyclophosphamide or steroids will enable blockade of the immune mediated toxicity without also diminishing its therapeutic value. Further studies examining methods to control the severe toxicity associated with high doses of IL-2 are needed. The future role that IL-2 may play in treating cancer is unclear. Whether IL-2 alone can have significant antitumor activity may depend on factors such as tumor bulk, the patient's inherent ability to generate cytotoxic cells or the susceptibility of a particular malignancy. As such further studies will need to examine the importance of dose, timing, schedule, method of IL-2 administration as well as tumor burden in a wide variety of cancers.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1985

Anaplastic Wilms' tumor: clinical and pathologic studies.

A review of almost 1,200 children participating in the first and second National Wilms' Tumor Study (NWTS-1 and -2) has demonstrated a number of significant differences in the clinical presentation and response to therapy of anaplastic and nonanaplastic Wilms' tumor. Compared to their counterparts, children with anaplastic Wilms' tumor were generally one to two years older at diagnosis, more were non-white, and more had lymph node metastases at diagnosis. Consistent with previous studies, children with anaplastic Wilms' tumor survived for a significantly shorter time than those with non-anaplastic Wilms' tumor. A hopeful outlook, however, was suggested by the NWTS-2 experience since the more aggressive chemotherapies used in this study appear to have substantially improved the survival of patients with diffusely anaplastic tumors. Also, the survival of NWTS-2 patients with anaplastic Wilms' tumor was determined in part by clinicopathologic stage. It may be possible therefore to refine therapy according to stage so as to provide children with localized disease a chance for cure with fewer untoward treatment-related sequelae.

Anaplasia↗
PubMed1984

Abdominal relapses in irradiated second National Wilms' Tumor Study patients.

Ten of 259 (3.8%) irradiated patients with group 2 and 3 tumors in the second National Wilms' Tumor Study experienced initial clinical relapse either in the operative site or elsewhere in the abdomen, excluding the liver and opposite kidney. Analysis of factors associated with abdominal recurrences has shown the independent significance of unfavorable histology, field size of the radiotherapy portals, and a postoperative delay of ten or more days before starting irradiation.

Abdominal Neoplasms↗
PubMed1984

Mechanisms involved in the hyperglycemic response induced by clonidine and other alpha-2 adrenoceptor agonists.

Clonidine induced a dose-dependent hyperglycemic response in fed rats, a minimal hyperglycemic response in 48-hr fasted rats and had no effect on blood glucose in 16-hr fasted, streptozotocin-diabetic rats. At a dose of 0.1 mg/kg, there was an equivalent hyperglycemic response in fed rats whether clonidine was administered orally, i.v. or i.p. A hyperglycemic effect was also observed with the central and peripheral alpha-2 adrenoceptor agonist, guanabenz (0.1 mg/kg i.v.). In contrast, 2-(3-4-dihydroxyphenylimino) imidazoline, an alpha-2 agonist which does not penetrate into the central nervous system, caused a lowering of blood glucose at the same dose. The hyperglycemic response induced by clonidine was partially inhibited by the selective alpha-2 antagonists, yohimbine and rauwolscine, and the nonselective alpha antagonist, phentolamine. The hyperglycemic response induced by clonidine was not affected by the selective alpha-1 adrenoceptor antagonists, prazosin or corynanthine. Methoxamine, an alpha-1 agonist, had no effect on clonidine-induced hyperglycemia. The hyperglycemic response to clonidine was partially inhibited by 3-mercaptopicolinic acid, an inhibitor of gluconeogenesis, but was not affected by pretreatment with the H2-histamine receptor antagonist, metiamide, the prostaglandin syntheses inhibitor, idomethacin, or the beta adrenoceptor antagonist, propranolol. These results suggest that 1) the hyperglycemic response induced by clonidine and other alpha-2 adrenergic agonists is mediated by alpha-2 adrenergic receptors located within the central nervous system and 2) clonidine-induced hyperglycemia is effected, in part, by enhanced gluconeogenesis.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Comparison of spontaneous and induced mutation rates in an immortalized human bronchial epithelial cell line and its tumorigenic derivative.

To determine the relationship between neoplastic transformation and increased genetic instability, spontaneous and induced mutation rates were compared in a nontumorigenic, immortalized human bronchial epithelial cell line (NL20) and a tumorigenic cell line (NL20T) spontaneously derived from the NL20 line. Using the hypoxanthine phosphoribosyltransferase (HPRT) locus as a marker for determining mutation rate, fluctuation analysis was utilized to evaluate the spontaneous mutation rate. Induced mutation rates were determined for each cell line after N-methyl-N'-nitro-N-nitrosoguanidine exposure. Both the spontaneous and induced mutation rates were noted to be significantly higher in the nontumorigenic NL20 cell line. These findings suggest that increasing genetic instability, as measured by spontaneous or induced mutation rate in the HPRT locus, does not correlate with tumorigenicity in these cells.

Adult↗