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Biomedical subjects

E K Rowinsky

Publications and source records attributed to E K Rowinsky.

155 records · Page 9Linked to original sources
PubMed1988

Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol.

Taxol, a diterpenoid plant product that enhances the polymerization of tubulin, is currently entering clinical trials in the treatment of human leukemia. In order to develop an in vitro assay to predict tumor sensitivity to taxol, human leukemic cell lines were exposed to clinically achievable concentrations of taxol for relevant exposure periods. Changes in microtubules visualized by indirect immunofluorescence were compared to drug sensitivity measured by a clonogenic assay. Taxol produced either multiple mitotic asters in G2/M or microtubule bundling throughout the cell cycle. In cells that were relatively resistant to taxol, microtubule bundling was reversible while microtubule bundling in relatively sensitive cells persisted in the presence or absence of taxol. In contrast, aster formation was unrelated to cytotoxicity in any cell line. In the future, these microtubule effects may be useful in predicting the chemotherapeutic efficacy of taxol.

Alkaloids↗
PubMed1988

Clinical pharmacology of oral and i.v. N-methylformamide: a pharmacologic basis for lack of clinical antineoplastic activity.

N-Methylformamide (NMF) has been an agent of considerable interest to oncologists because of its broad spectrum of preclinical antitumor activity, tumor-differentiating abilities, and radiosensitizing and chemosensitizing properties. In this report, the pharmacokinetics of NMF are described, based on data from two phase I studies exploring both iv and oral routes of administration. Mean peak NMF plasma concentrations at recommended phase II doses were 0.46 mmol/L for NMF administered orally, 600 mg/m2 three times/week X 4 weeks every 6 weeks, and 2.78 mmol/L for NMF administered as a weekly iv bolus at 2,000 mg/m2 X 3 weeks every 4 weeks. These NMF concentrations were significantly lower than the concentrations that have been demonstrated to induce antineoplastic and relevant biologic effects in preclinical studies. Plasma disappearance curves were biphasic in the majority of patients; however, 25% of the curves were best fit by a monoexponential kinetic model. Mean alpha half-life and beta half-life values (+/- SE) were 10 +/- 2 and 732 +/- 93 min, respectively. Volumes of distribution for the theoretical central compartment (Vc) and at steady-state (Vss) were 13.8 +/- 1.1 L/m2 and 18.7 +/- 1.1 L/m2, respectively. The mean plasma clearance of NMF was 19.1 +/- 2.1 mL/min per square meter, and the relative contributions to parent compound disposition by respiratory and renal routes were insignificant. No metabolites were identified. Gastrointestinal absorption of oral NMF was rapid and nearly complete; oral bioavailability was calculated to be 0.87. Pharmacodynamic associations were observed between the magnitude of the area under the plasma disappearance curves and hepatotoxicity, the dose-limiting toxic effect of iv NMF, and the symptom complex of nausea, vomiting, and malaise, which precluded dose escalation of oral NMF.

Administration, Oral↗
PubMed1987

Prolonged infusion of hexamethylene bisacetamide: a phase I and pharmacological study.

Hexamethylene bisacetamide (HMBA, NSC 95580), a potent polar-planar differentiating agent in vitro, was studied in a phase I trial as a 10-day continuous infusion administered every 4 weeks. Since preclinical evidence had demonstrated that the duration of HMBA exposure was an important variable in the induction of differentiation, and HMBA steady-state concentrations (Css) achieved during 5-day infusions were minimally effective at inducing in vitro differentiation, this study was conducted to evaluate the feasibility of maintaining HMBA Css for 10 days similar to levels achieved and maintained for 5 days. Twelve patients received 17 evaluable courses at three dose levels, 12, 15.8, and 20 g/m2/day. Platelet toxicity limited further dose escalation. Mean nadir and percentage of decrement in platelet counts were 175,000/microliter and 66%, and 43,500/microliter and 83%, at 15.8 and 20 g/m2/day, respectively. In this 10-day study, the percentage of decrement of platelet counts was linearly related to mean HMBA Css and to the area under the plasma concentration versus time curve (AUC). However, when combined platelet and pharmacological data from both 5- and 10-day studies were analyzed, it was apparent that the duration of HMBA exposure was an additional significant variable in predicting the magnitude of thrombocytopenia. Renal and metabolic toxicities that precluded dose escalation in previous 5-day trials of HMBA were mild and insignificant in this study. Mean HMBA Css were 0.65 +/- 0.09 mmol/liter at 15.8 g/m2/day, and 0.99 +/- 0.22 mmol/liter at 20 g/m2/day. Depletion of intracellular polyamines in peripheral blood mononuclear leukocytes was noted during several courses that were associated with profound myelosuppression, but no clear relationships were apparent between the magnitude of polyamine changes and toxicity or between fluctuations in polyamines and the magnitude of mean HMBA Css values. Based on this study, the maximum tolerated and recommended phase II doses for HMBA administered on this schedule were 20 and 15.8 g/m2/d, respectively. The administration of HMBA by a ten-day infusion at the maximum tolerated dose resulted in the delivery of lower daily doses and lower HMBA Css than on the 5-day schedule. The major toxicities differed on these schedules with thrombocytopenia being most prominent on the 10-day schedule and metabolic and CNS toxicities on the 5-day schedule.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetamides↗
PubMed1987

Phase I trial of taxol in patients with advanced cancer.

Taxol is a unique plant-derived antineoplastic agent that appears to exert its cytotoxic effect by interfering with microtubule structure and function. In this phase I trial, in which the drug was given as a brief iv infusion every 3 weeks, the dose-limiting toxicity was leukopenia, with thrombocytopenia being seen much less frequently. Sensory neuropathy was frequently seen at the highest dosage, with numbness and paresthesias appearing in a glove-and-stocking distribution. In some cases, this appeared to be a cumulative effect. Total alopecia was common. Other toxic effects observed included nausea and vomiting, mucositis, myalgias, and phlebitis. The frequent occurrence early in the study of acute cardiovascular and pulmonary toxicity suggestive of hypersensitivity reactions was decreased in frequency and severity by prolonging the infusions and premedication with corticosteroids and antihistamines. Two heavily treated patients appeared to respond to this agent, one with non-small cell lung cancer and one with ovarian cancer. Based on these data, we recommend a starting dose in phase II trials of 212 mg/m2 in patients with minimal prior therapy and 170 mg/m2 in heavily treated patients. At least initially, these trials should be carried out in institutions familiar with the use of this drug.

Alkaloids↗
PubMed1987

Hexamethylene bisacetamide-induced cutaneous vasculitis.

Nonthrombocytopenic purpura developed in a patient receiving hexamethylene bisacetamide, a tumor-differentiating agent in vitro that is in phase I clinical trials. Histopathological examination revealed features of leukocytoclastic vasculitis with deposition of IgA and complement in the dermal vasculature. Leukocytoclastic vasculitis, an extremely rare complication of therapy with antineoplastic agents, is reported to alert others using this compound of this association.

Acetamides↗
PubMed1986

Massive adrenal hemorrhage secondary to metastatic lung carcinoma.

The adrenal glands are frequently metastatic sites of lung and other primary neoplasms. These metastases are usually clinically occult and secondary adrenal hemorrhage is extremely rare. Two patients who developed massive adrenal hemorrhage secondary to metastatic lung carcinoma to the adrenal glands are presented.

Adenocarcinoma↗
PubMed1986

Phase I and pharmacologic study of hexamethylene bisacetamide in patients with advanced cancer.

Hexamethylene bisacetamide (HMBA, NSC 95580) has been demonstrated to be the most effective of the known and studied polar-planar compounds at inducing differentiation in a wide variety of leukemic and nonleukemic cell lines. Although HMBA demonstrated no antineoplastic activity in preclinical testing, it was selected for clinical development on the basis of its potent differentiating capabilities in vitro. In this phase I study, HMBA was administered as a continuous five-day infusion every 3 weeks to patients with advanced cancer. Twenty-three patients received 35 evaluable courses at doses that ranged from 4.8 to 33.6 g/m2/d. Dose-limiting toxicities included renal insufficiency, a hyperchloremic metabolic acidemia/acidosis, and CNS toxicities manifested by agitation and delirium, which progressed to coma in one patient who developed concomitant renal insufficiency. Moderate myelosuppression, mucositis, nausea, and vomiting were also observed. The pharmacokinetics of HMBA best fit a single compartmental model and disposition is primarily by renal elimination. Renal excretion of HMBA and of the primary metabolite, 6-acetoamidohexanoic acid, together account for the disposition of 66% to 93% (mean, 74%) of the infused drug. Based on this trial, the maximum tolerated and recommended phase II doses for HMBA administered on this schedule are 33.6 and 24 g/m2/d, respectively. However, since steady-state HMBA levels at these doses were in the range of 1 to 2 mmol/L, only approaching the lower limit demonstrated for in vitro differentiating effectiveness, and because of evidence suggesting that the exposure period is an important variable in the induction of differentiation, additional studies examining longer periods of infusion are warranted.

Acetamides↗
PubMed1985

Spontaneous pneumothorax following thoracic irradiation.

Spontaneous pneumothorax has only very rarely been reported to occur following thoracic irradiation. Four patients who developed this complication following radiation therapy are presented and the literature is reviewed. Spontaneous pneumothorax following thoracic irradiation tends to be recurrent, occasionally bilateral, and in most reported cases, occurs in patients who develop roentgenographic evidence of radiation fibrosis after treatment with mantle-shaped portals for Hodgkin's and non-Hodgkin's lymphomas. Re-expansion often occurs without intervention.

Adolescent↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer.

Topotecan, a semisynthetic water-soluble analog of camptothecin, is the first topoisomerase I-directed drug to enter clinical trial in the United States in over 20 yr. In this study, 30-min infusions of topotecan were administered daily for 5 days every 3 weeks at doses ranging from 0.5 to 2.5 mg/m2. Topotecan is reversibly hydrolyzed in a pH-dependent reaction in aqueous solutions to the ring-open hydroxy acid. The disposition of the closed ring lactone has been studied in 26 patients, and the disposition of both lactone and hydroxy acid has been studied in 12 patients. The clearance rate for topotecan lactone was 1220 ml/min/m2, with a range of 300-4760 ml/min/m2. The clearance rate for total topotecan (lactone and hydroxy acid) was 493 ml/min/m2, with a range of 163-815 ml/min/m2. A model for the disposition of lactone and hydroxy acid incorporating both reversible hydrolysis and elimination was developed. We have shown that topotecan is partially hydrolyzed prior to administration in parenteral solutions, and that clearance of the parent compound proceeds in vivo by conversion to hydroxy acid and elimination. Renal clearance accounted for 30 +/- 18% of drug elimination in patients. The relationship between topotecan dose and myelotoxicity is well fit by a sigmoidal Emax model, as is the relationship between total topotecan area under the concentration-time curve and myelotoxicity. The disposition of topotecan was also studied in mice. The clearance rate for total topotecan in mice was 330 ml/min/m2 after administration of topotecan lactone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗