High-dose cisplatin in hypertonic saline: reduced toxicity of a modified dose schedule and correlation with plasma pharmacokinetics. A Northern California Oncology Group Pilot Study in non-small-cell lung cancer.

Although increased efficacy has been described with a five-day schedule of high-dose cisplatin (CDDP) in hypertonic saline, severe myelosuppression and cumulative neurotoxicity have limited the usefulness of this therapy. In order to evaluate a possible dose-response relationship in non-small-cell lung cancer (NSCLC), 17 patients with metastatic disease were treated with a modified dose schedule delivering the same total dose (200 mg/m2) in a divided day 1 and 8 schedule. During a pilot study, a total of 47 cycles of therapy were administered, with a median of three cycles per patient and a median total cumulative dose of 600 mg/m2. Nine of 17 patients received at least 600 mg/m2. While nephrotoxicity was similar to previous reports of the five-day schedule, the incidence and severity of myelosuppression and peripheral neuropathy were markedly reduced. Using this modified schedule, severe myelosuppression did not occur. Clinically severe peripheral neuropathy developed in only one patient (6%). The overall response rate was 47% (eight of 17 patients). Plasma platinum pharmacokinetics during five cycles of the modified day 1 and 8 schedule were compared with pharmacokinetics of the five-day schedule. Accumulation of plasma ultrafiltrate platinum occurred in the five-day schedule, but not in the day 1 and 8 schedule. This difference in pharmacokinetics is one possible explanation for the reduced toxicity of this modified schedule. Although the degree of activity seen in this pilot study is encouraging, the efficacy of high-dose CDDP in NSCLC remains to be defined. In view of reduced myelosuppression and neurotoxicity, further trials with this modified schedule are indicated.

Serum tamoxifen concentrations in the athymic nude mouse after three methods of administration.

The athymic nude mouse has been used as an in vivo model for pharmacologic studies of the antiestrogen, tamoxifen. We have examined the steady-state serum tamoxifen concentrations achieved in mice with s.c. slow-release pellets, s.c. injections, and i.p. injections, in an attempt to identify a method that would yield serum levels similar to those observed in patients receiving tamoxifen therapy. Tamoxifen and tamoxifen metabolites were examined by a high-performance liquid chromatography assay which has a sensitivity of 8 ng/ml. Tamoxifen metabolites were not observed with any dose or schedule. After slow-release pellets containing 5 or 25 mg tamoxifen no tamoxifen was detectable, even after 2 weeks of treatment. Very low levels (0.07 microM) were found with 50-mg pellets. Tamoxifen was also not detected either with daily s.c. injections of 500 micrograms/mouse or with i.p. injections of 2.5 mg/kg. However, daily s.c. injections of 1000 micrograms or i.p. injections of 25, 50, or 100 mg/kg resulted in tamoxifen concentrations ranging from 0.21 to 0.51 microM which are similar to those observed in patients. Thus, clinically relevant tamoxifen concentrations can be achieved in the nude mouse with either of these methods of administration.

Preliminary observations of intraperitoneal carboplatin pharmacokinetics during a phase I study of the Northern California Oncology Group.

The pharmacokinetic behavior of carboplatin administered by the i.p. route at a dose of 200 mg/m2 was studied during five courses of therapy in four patients with ovarian cancer. A regional pharmacologic advantage was noted with carboplatin administered by this route, with peak peritoneal fluid concentrations 18-fold those in plasma, and area under the curve (AUC) for the peritoneum showing a 18-fold and 6-fold increase over plasma AUC at 4 and 24 h, respectively. The mean residence time of total platinum in the peritoneum was 4.7 h. Approximately 10% and 40% of plasma platinum was protein bound at 4 and 24 h after treatment, respectively, whereas peritoneal fluid platinum showed minimal protein binding. Peak plasma platinum levels were comparable to those recorded in previous studies with i.v. doses of carboplatin. Peritoneal clearance of carboplatin in these four patients appeared to be less than that previously reported for cisplatin. Further studies are in progress with higher doses of i.p. carboplatin.

Enzyme-linked immunosorbent assay (ELISA)-based quantification and identification of in vitro enzyme-catalyzed glycosphingolipid synthesis and degradation products with carbohydrate sequence-specific monoclonal antibodies.

A new method has been developed to monitor glycosyltransferase and glycosylhydrolase activities. Reaction product identification and quantification are accomplished simultaneously with an enzyme-linked immunosorbent assay (ELISA) using carbohydrate sequence-specific monoclonal antibodies. beta-Galactosyltransferase and alpha-galactosidase reactions were used to illustrate the salient features of the method. These include simple product identification and quantification, no detergent requirement, consumption of small amounts of reagents, and no use of radioisotopes. Furthermore, it is possible to measure substrate disappearance or product formation with this method. Enzyme characteristics such as Km, Vmax, divalent cation requirement, and pH optimum were investigated with this new method.

Ultrafiltrate and total platinum in plasma and cerebrospinal fluid in a patient with neuroblastoma.

Ultrafiltrate and total plasma and cerebrospinal fluid (CSF) platinum concentrations were examined in a patient with neuroblastoma following a 2-hour infusion of 120 mg/m2 of cisplatin. Total plasma platinum was 93.4% bound, while the ultrafiltrate of plasma accounted for the remaining 6.6%. The CSF ultrafiltrate resulted in equivalent concentrations of platinum to total CSF platinum. CSF concentrations were 2.9% of the total plasma platinum and 43.5% of the ultrafiltrate plasma platinum 2 hours after the end of the infusion.