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Biomedical subjects

E S Casper

Publications and source records attributed to E S Casper.

At least 91 records · Page 5Linked to original sources
PubMed1984

Phase I evaluation of a biochemically designed combination: PALA, thymidine, and 5-FU.

Fifteen patients with advanced solid tumors participated in a phase I study of a biochemically designed combination chemotherapy program which employed PALA and thymidine (TdR) with 5-FU. PALA (250-2000 mg/m2) was given 24 hours before a 90-minute iv infusion of TdR (45 g). 5-FU (100-150 mg/m2) was given as a rapid iv injection 30 minutes after beginning the TdR infusion. This three-drug treatment was repeated once weekly for 3 weeks. Neurotoxicity, manifested as dizziness, lethargy, and confusion, was dose-limiting. Myelosuppression was noted at all dose levels, as was mild to moderate mucositis and diarrhea. Further clinical evaluation of this combination does not appear to be warranted.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1983

Cisplatin, vindesine and bleomycin (CVB) combination chemotherapy of advanced non-small cell lung cancer.

Fifty-four patients with advanced squamous, large-cell or adeno-carcinoma of the lung were treated with a three drug regimen of high-dose cisplatin, vindesine and a four-day bleomycin infusion (CVB). All patients had measurable disease; none had previously received chemotherapy. Of 52 patients evaluable for response, 20 (38%) had complete or partial remissions. The median duration of remission was 8 months (range, 6 1/2-19+ months), with eight patients continuing in remission. The median duration of survival for responding patients was 16 months versus five months for nonresponding patients (P greater than 0.001). Toxicity included mild to moderate myelosuppression, peripheral neuropathy, and nephrotoxicity, and was generally manageable. The addition of a four-day bleomycin infusion did not appear to offer a significant advantage over the combination of high-dose cisplatin and vindesine in the treatment of NSCLC. The response rate and survival duration produced by the CVB protocol were similar to those reported for the two-drug combination of vindesine and high-dose cisplatin.

Adenocarcinoma↗
PubMed1983

Therapeutic utility of utilizing low doses of N-(phosphonacetyl)-L-aspartic acid in combination with 5-fluorouracil: a murine study with clinical relevance.

Doses of N-(phosphonacetyl)-L-aspartic acid (PALA) lower than those required for therapeutic activity against the spontaneous murine breast tumor (BALB/c X DBA/8 F1) were found to produce significant depression in uridine triphosphate pools in the tumor. Using such low, nontherapeutic, but biochemically active doses of PALA in combination with 5-fluorouracil (FUra(, it was possible to maintain the dose of FUra at its full maximum tolerated single agent dose. In comparison with the maximum tolerated dose of FUra alone, the combination of FUra plus low-dose PALA produced a significant increase in the level of tumor FUra-containing RNA, only a slight increase in intestinal FUra-containing RNA, and no increase in bone marrow FUra-containing RNA. These biochemical results correlated with the therapeutic findings of significantly increased antitumor activity without an increase in host toxicity. A review of currently reported PALA plus FUra clinical protocols reveals that the experimental parameters which have produced successful therapeutic results in the laboratory (i.e., a low-PALA:high-FUra dosage ratio) have not yet been translated into clinical trial. Final judgment on the clinical efficacy of PALA:FUra combinations must await the results of proposed low-PALA:high-FUra clinical trials.

Animals↗
PubMed1983

Phase I trial of PCNU.

In a phase I trial, 28 patients with advanced solid tumors were given PCNU daily for 5 days by iv infusion over 20 minutes at 6-week intervals. The total dose for each course ranged from 25 to 150 mg/m2 in six escalation steps. Myelosuppression was dose-limiting, with a platelet count depression regularly observed at doses of greater than or equal to 82.5 mg/m2. Leukopenia occurred only at higher doses. Nausea was uncommon, and vomiting did not occur. There were no adverse drug-related effects on renal or hepatic function. No antitumor activity was observed. A dose range of 100-125 mg/m2 iv for each 5-day course (20-25 mg/m2/day) is recommended for phase II studies.

Adenocarcinoma↗
PubMed1983

Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer.

4-Demethoxydaunorubicin (4-DMDR), an anthracycline analogue available in i.v. and p.o. form, has shown significant antitumor activity in murine tumor models while producing less cardiac toxicity than doxorubicin at equimyelotoxic doses. Phase I and clinical pharmacology studies of the i.v. and p.o. preparation were performed. With i.v. 4-DMDR, consistent myelosuppression was observed at a dose of 15 mg/sq m at a median Day 15; mild nausea and vomiting were observed in 9% of all treatment courses. In patients given p.o. 4-DMDR, myelosuppression occurred at median Day 14 in 10 of 12 patients given 50 mg/sq m. Nausea and vomiting occurred in 25% of all treatment courses, and dividing the dose over 3 days did not decrease the incidence. Alopecia occurred in 13% of evaluable patients treated with the i.v. preparation and 30% of evaluable patients treated p.o. No stomatitis was observed with either preparation, and no patient developed clinical signs of congestive heart failure. Pharmacokinetic studies were performed with both preparations and revealed prolonged plasma levels of the 13-hydroxy metabolite 4-DMDR-ol. The suggested starting dose for Phase II studies is 12.5 mg/sq m given every 21 days for i.v. 4-DMDR with dose escalation by 2.5 mg/sq m in the absence of myelotoxicity. For p.o. 4-DMDR, the suggested starting dose is 40 mg/sq m given every 21 days with escalation by 10 mg/sq m if no myelotoxicity is observed.

Administration, Oral↗
PubMed1983

Ip cisplatin in patients with malignant ascites: pharmacokinetic evaluation and comparison with the iv route.

Ip chemotherapy may be useful in managing patients with malignant ascites. This approach should result in a high concentration of drug at the site of disease, while the plasma concentration and therefore systemic toxicity remain low. Six patients with malignant ascites were treated with cisplatin at a dose of 60 mg/m2. Three patients received the drug iv; one of these patients and three other patients were treated with ip cisplatin. Platinum concentrations in plasma, ascites, protein-free ultrafiltrates of plasma and ascites, and urine were assayed by flameless atomic absorption spectrophotometry. The area under the concentration x time curve for ultrafilterable platinum in ascites was 30 times greater after ip administration of cisplatin than after iv cisplatin. Ip cisplatin can be administered safely to patients with malignant ascites and may be useful in patients with minimal residual intraperitoneal disease, particularly ovarian carcinoma.

Adenocarcinoma↗
PubMed1983

Phase I study of tricyclic nucleoside phosphate.

A phase I study of tricyclic nucleoside phosphate was conducted in 20 adults with advanced cancer. Tricyclic nucleoside phosphate was given as an iv infusion over 15 minutes once every 3 weeks; the doses ranged from 25 to 350 mg/m2. Beginning at a dose of 250 mg/m2, hyperglycemia and elevation of hepatocellular enzymes were observed; at a dose of 350 mg/m2, two patients developed irreversible liver damage. Patients at all dose levels experienced reduction in serum phosphorus; reduction of serum calcium was noted only with the two highest doses. Nausea and vomiting occurred occasionally. Myelosuppression was not a prominent toxic effect. No major therapeutic responses were noted. Further clinical trials employing this schedule are probably not warranted.

Acenaphthenes↗
PubMed1983

Phase I and clinical pharmacological evaluation of biochemical modulation of 5-fluorouracil with N-(phosphonacetyl)-L-aspartic acid.

5-Fluorouracil (FUra) is a clinically useful antineoplastic agent. Preclinical studies suggest that the therapeutic effects of FUra can be enhanced by pretreatment with N-(phosphonacetyl)-L-aspartic acid (PALA), an inhibitor of aspartate transcarbamylase. The objective of treatment with PALA is to increase the activation of FUra by inhibiting the normal pathway of de novo pyrimidine biosynthesis. Theoretically, the optimal dose of PALA should produce effective blockade of this pathway without increasing toxic effects of FUra. Using pyrazofurin-induced orotic aciduria and orotidinuria as a measure of this pathway, it as determined that PALA (250 mg/sq m) is effective in inhibiting total-body pyrimidine synthesis. Sixty-eight adult patients with cancer were treated with combinations of PALA and FUra. High doses of PALA (1 to 2 g/sq m) prevented the use of full dosage of FUra; however, PALA (250 mg/sq m) can be administered 24 hr before FUra (750 mg/sq m) once weekly for at least 3 weeks. The toxicity observed using that combination of doses was mild to moderate myelosuppression, mucositis, diarrhea, nausea, and vomiting. Further clinical studies are warranted.

Adult↗
PubMed1982

Neurotoxicity of the pyrimidine synthesis inhibitor N-phosphonoacetyl-L-aspartate.

PALA (N-phosphonoacetyl-L-aspartate) impairs de novo pyrimidine biosynthesis by inhibiting the enzyme aspartate transcarbamylase. During cancer chemotherapy trials the drug was given by weekly intravenous infusion. Seizures developed in 9 (11%) of the first 80 patients to receive a total dose of 9 gm/m2 or more. Seven of the affected patients had structural brain lesions; they developed seizures at a lower total dose (median of 16.4 gm/m2) than the 2 patients without clinically detectable brain lesions (115 to 130 gm/m2). Reversible encephalopathy was observed in 6 (7.5%) additional patients without clinically detectable cause other than PALA. Both seizures and encephalopathy began after the second dose of PALA or later. Experiments in rats demonstrated similar delayed-onset seizures after two or three combined systemic and intracerebral doses of PALA at 4-day intervals. Concurrent administration of uridine or carbamyl aspartate prevented the development of seizures in rats, indicating that pyrimidine starvation of the central nervous system was responsible for PALA neurotoxicity.

Adult↗
PubMed1982

Specific determination of pentamethylmelamine and its demethylated metabolites in human plasma by high pressure liquid chromatography.

Pentamethylmelamine (PMM) and its demethylated metabolites tetra-N2246, tri-N246 and tri-N224 have comparable relative antitumor potencies in animal systems. We have developed a sensitive and specific high pressure liquid chromatography (HPLC) assay for these compounds in the plasma of patients receiving pentamethylmelamine, a cytotoxic S-triazine derivative now undergoing clinical trials. The method involves analysis of an ethyl acetate extract of plasma by a high pressure liquid chromatograph containing a reverse-phase column and ultraviolet detection at 240 nm. The mobile phase is acetonitrile and KH2PO4 buffer (pH 5.5); gradient elution over 25 min yields relative retention times to hexamethylmelamine as internal standard of 0.36, 0.40, 0.54 and 0.70 for tri-N246, tri-N224, tetra-N2246 and PMM. The lower limit of sensitivity for each is 300 ng/ml. Pharmacokinetic studies on four patients receiving a 24-h infusion of PMM (doses 900-3000 mg/m2) showed a mean terminal half-life of PMM of 101 +/- 28 (SD) min, a mean volume of distribution of 2036 +/- 75 ml/kg, and a metabolic clearance rate of 14.2 +/- 3.7 (ml/min)/kg. Mean areas under the plasma-vs-time curves of tri-N246, tri-N224 and tetra-N2246 were 126%, 41% and 56% of PPM, demonstrating extensive formation of these metabolites in man.

Altretamine↗
PubMed1982

Phase II trial of VP-16-213 in non-small-cell lung cancer.

Fifty-one patients with metastatic non-small-cell lung cancer (NSCLC) were treated with VP-16-213 (4'-demethylepipodophyllotoxin) during a phase II trial. Of the 49 patients who had adequate trials, 2 patients achieved a partial response (PR), for an overall 4% major response rate. The median Karnofsky performance status (PS) was 80%; 85.7% of patients had adenocarcinoma and 14.2% had epidermoid carcinoma. Prior treatment with chemotherapy may have adversely affected response rate; the two responses occurred among the 25 previously untreated patients, while no responses were seen in patients who had previously received chemotherapy. Myelosuppression was the most frequent side effect and two drug-related deaths due to septicemia occurred. Other toxic effects noted included anorexia, nausea and hypotension during drug infusion. We conclude that VP-16-213 has minimal activity as a single agent in NSCLC.

Adenocarcinoma↗
PubMed1981

Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: A randomized trial investigating two dosage schedules.

Eighty-five patients with advanced squamous carcinoma or adenocarcinoma of the lung were randomly assigned to receive vindesine with either high dose (120 mg/m2 of body surface area) or low dose (60 mg/m2) cisplatin. All patients had measurable disease and had not previously received chemotherapy. The response rate was similar with both treatments (43% complete and partial remission rate), but the high dose cisplatin regimen was superior to the low dose in median duration of response (12 versus 5.5 months; p = 0.05) and in median survival for responding patients (21.7 versus 10 months; p = 0.02). Myelosuppression was generally not a treatment problem; peripheral neuropathy and moderate azotemia were the major dose-limiting toxicities. With improved survival and response rates over those reported for conventional regimens, this combination of new agents supports the approach of new drug investigation in patients with lung cancer and the importance of the incorporation of active new agents into initial chemotherapy regimens.

Adenocarcinoma↗
PubMed1981

Phase I and pharmacological studies of pentamethylmelamine administered by 24-hour intravenous infusion.

A Phase I study of pentamethylmelamine (PMM) was conducted, administering the drug as a 24-hr i.v. infusion once weekly for 3 weeks. Doses ranged from 80 to 3000 mg/sq m/week. Twenty-six evaluable patients received a total of 30 courses of PMM. The median performance status of the patients was 60% (range, 40 to 90%), and the median age was 58 years (range, 43 to 72 years). The highest tolerated dose was 2000 mb/sq m/week. Nausea and vomiting were the dose-limiting toxicities; myelosuppression was neither consistent nor severe. One objective response lasting 10 months was noted in a patient with renal cancer. Pharmacokinetic studies using [ring-14C]PMM demonstrated a postinfusion half-life of 14C of approximately 12 hr, with the majority of the radiolabel excreted in the urine. PMM was introduced as a parenteral form of hexamethylmelamine. The present schedule does not permit administration of PMM in a dose greater than the tolerated dose of hexamethylmelamine and does not appear to offer an advantage over the p.o. use of the parent compound.

Adult↗
PubMed1981

Clinical phase I study of aclacinomycin A by evaluation of an intermittent intravenous administration schedule.

Aclacinomycin A (ACM) is an anthracycline antibiotic recently introduced into clinical trials because of its reduced cardiac toxicity in animal models relative to Adriamycin and daunomycin. This Phase I study of ACM was conducted to determine a dose suitable for i.v. administration on an every-3-week schedule. Twenty-five adult patients with solid tumors were treated with doses of ACM ranging from 60 to 120 mg/sq m i.v. every 3 to 4 weeks. Myelosuppression was the dose-limiting toxicity, but the degree and timing of blood count depression were variable at each dose level. Nausea and vomiting were seen at myelosuppressive doses, but mucositis was rare. Alopecia was seen in approximately one-third of the patients. There was no acute cardiac toxicity, but cumulative cardiac injury could not be evaluated in this trial. There were no major objective responses in three patients who had measurable disease. The recommended doses of ACM for Phase II studies are 100 mg/sq for good-risk patients and 80 mg/sq m for patients who are heavily pretreated or who have a poor performance status.

Aclarubicin↗