The practical benefits of pharmacokinetics in the use of antineoplastic agents.
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Animals↗
Biomedical subjects
C Erlichman
Publications and source records attributed to C Erlichman.
Application of a simple competitive protein-binding assay technique to the pharmacokinetics of N-(phosphonacetyl)-L-aspartate in humans.
A competitive protein-binding assay for N-(phosphonacetyl)-L-aspartate (PALA) using aspartate transcarbamylase as the receptor protein and [14C]PALA as the radioactive ligand is described here and has been applied to study the pharmacokinetics of PALA in humans. A protein-free ultrafiltrate of plasma, prepared by centrifugation of 1-ml samples through Amicon Centriflo membrane cones, was used in the assay, which had a maximun sensitivity of 0.7 microM PALA in plasma. At this level, the coefficient of variation was less than 10%. Comparison of the competitive binding assay to a gas chromatographic-mass spectrometric technique shows that the two methods yield equivalent results in the concentration range of 1 microM to 1 mM. However, the competitive binding assay possesses practical advantages because of its simplicity and the ease with which multiple samples may be assayed. PALA disappearance from plasma was studied in seven patients and was found to be consistent with a two-compartment open model. The t1/2 alpha (elimination half-life for initial phase) and t1/2 beta (elimination half-life for terminal phase) were 0.93 +/- 0.73 (S.D.) hr and 4.82 +/- 1.48 hr, respectively. The cumulative urinary excretion of PALA int two patients was 70 and 90% of the administered dose 16 hr after the infusion was completed.
Aspartate Carbamoyltransferase↗
Serum uridine levels in patients receiving N-(phosphonacetyl)-L-aspartate.
Serum uridine levels of N-(phosphonacetyl)-L-aspartate-treated patients from Phase 1 and continuing trials receiving 1000 to 2000 mg/sq m/day were measured by reverse-phase high-pressure liquid chromatography. For the five patients studied, the predose serum levels ranged from 2.6 to 64. microM, well within the normal range of 1.9 to 8.9 microM. All serum uridine levels decreased in the first 24 hr, but the drop was quite variable (7 to 65%). Uridine levels in all five patients remained being 37 to 85% at differing time points. The only patient to show a daily decrease was the only responder and the patient with the largest decrease. N-(Phosphonacetyl)-L-aspartate appears to have a limited reductive effect on human serum uridine levels.
Antimetabolites, Antineoplastic↗
Ectopic production of human chorionic gonadotropin: a case report.
The ectopic production of the beta-subunit of human chorionic gonadotropin (hCG) is described in a patient with an anaplastic carcinoma. After chemotherapy the marker decreased in a logarithmic fashion to undetectable levels but the neoplasm progressed and the patient died. The specificity of the beta-subunit of hCG is discussed. Discordance of the marker and clinical disease is pointed out, and several possible explanations are outlined. The lack of specificity of the beta-subunit of hCG and the discordance that it may exhibit means that its use in diagnosing and following disease progression may be limited.
Adult↗
Phase I trial of N-(phosphonacetyl)-L-aspartate.
A Phase I clinical trial of N-(phosphonacetyl)-L-aspartate, an antimetabolite which inhibits a key enzyme in the de novo pathway of pyrimidine biosynthesis, was conducted. N-(Phosphonacetyl)-L-aspartate was given as an i.v. 15-min infusion once daily for five days; cycles of treatment were repeated every three weeks. Thirty-four patients received treatment. Dose-limiting toxicity was observed at 1500 to 2000 mg/sq m/day and was manifested by skin rash, diarrhea, and stomatitis. Rash and diarrhea usually began during the first week of treatment and persisted up to Day 17 of a cycle of therapy. No consistent hematopoietic, hepatic, or renal toxicity was observed. One partial response in a patient with colon carcinoma was seen and continues at more than eight months. Stable disease was observed in three patients with colon carcinoma, two patients with hypernephroma, one patient with pancreatic carcinoma, and one patient with melanoma. The predictability and reversibility of toxicity and the suggestion of antitumor activity in humans are observations which support the further evaluation of N-(phosphonacetyl)-L-aspartate in Phase II studies.
Adolescent↗
Review of 154 patients with non-functioning pituitary tumors.
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Adenoma, Chromophobe↗
An evaluation of postoperative follow-up tests in colon cancer patients treated for cure.
BACKGROUND: Currently patients with colon cancer who are potentially cured by surgery are followed periodically with physical examinations, blood tests and imaging studies to detect tumor recurrence early, on the presumption that intervention can effect outcome. There is little information to indicate whether frequent visits to the doctor's office or frequent testing improves survival or quality of life. METHODS: Ninety-eight patients with resected stage B2, B3 or C (modified Astler-Coller) colon cancer who developed recurrent disease while enrolled in prospective adjuvant trials at Mayo Clinic sponsored by the North Central Cancer Treatment Group were studied to evaluate the utility of follow-up tests to detect the first recurrence of colon cancer and the outcome following various interventions for these recurrences. These patients had a history, physical examination, complete blood count, chemistry panel and chest x-ray approximately every 3-4 months in the 1st year and then every 6-12 months thereafter for a total of 5 years. Bowel evaluation was done at 6 months, 12 months and annually thereafter. In addition, a minority of patients had carcinoembryonic antigen (CEA) testing, and radioisotope liver scans at various intervals. RESULTS: Symptoms signaled the diagnosis of recurrent disease in 55 patients, physical examination in 4 patients, and abnormalities in chest x-ray in 18 patients. An elevated CEA was the initial abnormal test in 5 patients, abnormal liver scans in 5 patients, elevated liver function tests in 6 patients and laparotomy for other reasons in 2 patients. Hemoglobin, barium enema, and fecal blood testing were useful in 1 patient each. Thirty-one percent of recurrences were diagnosed between scheduled visits. In our series, histories, physical examinations, and chest x-rays led to the detection of 79% of the recurrences while liver function tests, liver scans and CEAs led to the detection of 16% of recurrences. Sixteen patients underwent resection for cure for their first recurrence; the diagnosis of recurrence was signaled by symptoms in 6 patients, chest x-ray in 6 patients and abnormal liver function tests, CEA, hemoglobin, and laparotomy for colostomy closure in 1 patient each. CONCLUSIONS: The majority of tumor recurrences were detected by symptoms, physical examinations and chest x-rays. Testing for asymptomatic tumor recurrences during the 1st follow-up year is likely to be much less fruitful for detecting resectable recurrences than testing patients in the 2nd through 4th follow-up years. Patients who had a disease recurrence in the 1st postoperative year were less likely to be candidates for curative intent surgery. Lower tumor grade at initial diagnosis correlated both with likelihood of undergoing secondary surgical resection and the chance of doing well following this. These data may be helpful for defining more appropriate follow-up test for detection of tumor recurrence in patients with resected colon cancer.
Adult↗
Novel agents in colorectal cancer.
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Antineoplastic Agents↗
Resistance of MGH-U1 bladder cancer spheroids to vincristine.
We compared the cytotoxicity of vincristine in MGH-U1 human bladder cancer cells growing as exponential monolayer culture, spheroids and xenografts. Cells treated as spheroids were resistant to vincristine as determined by clonogenic survival and growth delay. The spheroid population had a smaller proportion of cells in G2 + M than monolayer cells. Cell derived from increasing depths of the spheroid viable rim had similar cell cycle distribution characteristics and sensitivity to vincristine. Prolonged treatment of spheroid did not increase vincristine cytotoxicity significantly. When cells derived from spheroids were treated as monolayers, the cytotoxicity was the same as that of cells maintained as monolayer cultures. The vincristine resistance observed in spheroids was also observed in xenografted tumours treated in vivo. Vincristine decreased the clonogenic survival of xenografted cells at in vivo doses which were greater than the LD10 for the mice. The in vitro cytotoxicity of the xenografted tumours at these lethal doses was similar to that of cells treated as spheroids. We conclude that vincristine resistance in spheroids may be attributed in part to the small proportion of cells traversing mitosis but not to the development of intrinsic resistance by passage through spheroid growth. Our results are consistent with cell cycle kinetics and limited penetration contributing to vincristine resistance in spheroids. The spheroid system can serve as a model of in vivo cytotoxicity for antineoplastic agents with cell cycle phase specificity such as vincristine.
Animals↗
Effects of 5-fluorouracil and leucovorin in spheroids: a model for solid tumours.
We determined the cytotoxcity of 5FU alone or with leucovorin in MGH-U1 cells growing as monolayers or spheroids. The 5FU IC50 in spheroid and monolayers was 100 microM in both culture systems. The IC50 of 5FU and 5FU and 100 microM leucovorin in spheroids and monolayers was 100 microM and 50 microM, respectively. [H3]5 FU reached cells at all depths of the spheroid viable rim. Cells isolated from increasing depths of the spheroid viable rim demonstrated increasing resistance to 5FU. 5FU cytotoxicity is increased by leucovorin in monolayer but not spheroids, penetration is not limiting in 5FU cytotoxicity in spheroids and there is increasing resistance to 5FU in the viable rim.
Cell Division↗
Peripheral leukocytes as indicators of the enzymatic effects of N-(phosphonacetyl)-L-aspartic acid (PALA) on human L-aspartate transcarbamoylase (ATCase) activity.
The interaction of N-(phosphonacetyl)-L-aspartic acid (PALA) with L-aspartate transcarbamoylase (ATCase), the putative target for the antineoplastic activity of this drug, has been studied in the blood of patients participating in a phase I trial of PALA. ATCase activity in human blood is most abundant in granulocytes and lymphocytes; comparatively little activity is seen in erythrocytes. Utilizing peripheral leukocytes from patients given infusions of PALA, we find that leukocyte ATCase in inhibited rapidly and strongly. After cessation of therapy the rate of restitution of enzyme activity is slow: half-maximal restoration is achieved in about 280 hours. As a correlate of this gradual recovery of enzymatic activity, nanomolar concentrations of PALA are detectable in the plasma 2 weeks after infusion. The apparent Ki of PALA for leukocyte ATCase with carbamoyl phosphate as the variable substrate is 5 nM. Uptake of PALA into leukocytes in vitro is saturable and occurs at a moderate rate comparable to that measured in murine tumor cells. Correspondingly, inhibitory concentrations of PALA (approximately 10(-7) M) are found in the leukocytes of patients throughout the course of PALA treatment. It is concluded that although leukocytes are not targets for PALA toxicity, they may serve as accessible and pertinent indicators of the enzymatic effects of this new oncolytic drug.
Aspartate Carbamoyltransferase↗