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Biomedical subjects

R C Donehower

Publications and source records attributed to R C Donehower.

At least 109 records · Page 6Linked to original sources
PubMed1989

A phase I trial of trimetrexate glucuronate (NSC 352122) given every 3 weeks: clinical pharmacology and pharmacodynamics.

Trimetrexate glucuronate (TMTX), a non-classic folate antagonist, has been evaluated clinically on several schedules. We studied TMTX given as an i.v. bolus over 5-30 min every 3 weeks in 44 patients with advanced solid tumors; it was given at doses ranging from 20 to 275 mg/m2. The maximal tolerated dose (MTD) on this schedule is 220 mg/m2, which we also recommend as a starting dose for phase II studies in patients without extensive prior therapy. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for non-toxic patients. The principal dose-limiting toxicity was myelosuppression, although in some patients a flu-like syndrome precluded dose escalation. Significant rash and mucositis also frequently occurred in toxic patients. TMTX plasma concentrations were measured after the first dose and the data were fit by two- or three-compartment mammillary pharmacokinetic models. The TMTX clearance rate was 36.5 +/- 21 ml/min per m2 and did not change with dose; non-linearities with increasing dose were apparent in the steady-state volume of distribution (Vss) and in the terminal disposition half-life (t1/2). The difference between pre-treatment and nadir leucocyte counts was correlated with TMTX dose (r = 0.58; P = 0.0006) and with the area under the concentration vs time curve (AUC) (r = 0.41; P = 0.02). Pre-treatment plasma albumin concentrations correlated weakly with the nadir white blood count (r = -0.36; P = 0.047). Optimal schedules for the administration of TMTX have not been established and phase II trials using both bolus and daily X 5 schedules are under way.

Adult↗
PubMed1989

Demonstration of the cell cycle positions of taxol-induced "asters" and "bundles" by sequential measurements of tubulin immunofluorescence, DNA content, and autoradiographic labeling of taxol-sensitive and -resistant cells.

We used reliable and relatively inexpensive equipment to make sequential sets of measurements of antitubulin immunofluorescence, Feulgen staining, and autoradiography on the same cells. This was done to evaluate tubulin conformations, DNA content, and [3H]-thymidine incorporation in cell lines sensitive (HL60) and resistant (K562) to the novel anti-tubulin chemotherapeutic agent taxol. Numbers of cells with microtubule bundles have been found to correlate with sensitivity to taxol by clonogenic assay for several leukemic cell lines. We have found that cells with "asters" produced by taxol exposure are in mitosis and that cells with taxol-induced "bundles" are in G0/G1, S, and G2 phases. We further found that S-phase cells with microtubule bundles in both sensitive (HL60) and resistant (K562) cell lines were able to incorporate [3H]-thymidine after 4-hr exposure to taxol. As microtubule bundles and asters occur in cells of the same cell cycle phases in both lines, we conclude that the greater frequency of cells with microtubule bundles reported for sensitive cells after taxol treatment cannot result from drug exclusion nor from different effects of the drug on cell microtubules in these two leukemic lines.

Alkaloids↗
PubMed1989

In vivo cell growth and pharmacologic determinants of clinical response in acute myelogenous leukemia.

A predictable increase in the proliferative rate of malignant cells remaining after initial cytoreduction in vivo forms the rationale for timed sequential therapy (TST) with 1-B-D-arabinofuranosylcytosine (ara-C) for adult acute myelogenous leukemia (AML). The relationship between in vivo leukemic cell growth, intracellular ara-C metabolism, and clinical response to ara-C-containing TST was evaluated by comparing AML marrow cell growth kinetic and biochemical pharmacologic determinants obtained before therapy (day 0) and at the predicted peak of in vivo postdrug residual tumor proliferation (day 8). Serial measurements of DNA synthesis and net intracellular ara-C metabolism demonstrated marked increases in both determinants in day 8 residual tumor when compared with the pretreatment cells for newly diagnosed adults achieving complete remission but not for TST-refractory patients. The interrelationship of AML cell proliferation and biochemical pharmacology together quantitate cytotoxicity measured by both achievement and duration of remission and serve to predict eventual clinical outcome in response to TST with ara-C where both growth and favorable pharmacokinetics are intrinsic to the success of the drug schedule.

Adult↗
PubMed1988

Clinical and pharmacologic reappraisal of dichloromethotrexate.

Dichloromethotrexate (DCMTX) has been the subject of sporadic clinical development for the last 30 years. Although DCMTX was developed in hopes of discovering a more potent antifolate, the potential pharmacologic and toxicologic advantages of the analog have become of greater interest. This phase I and pharmacokinetic trial of DCMTX given on days 1, 8, and 15 every 28 days was undertaken to test these potential advantages. The maximally tolerated dose on this schedule was 980 mg/m2. Hepatic toxicity was dose limiting. Malaise, myelosuppression, and mucositis were also major toxic effects. The recommended dose for subsequent phase II studies of DCMTX administered on this schedule is 785 mg/m2 with a reduction to 625 mg/m2 for patients with a poor performance status or extensive prior therapy. Plasma disappearance curves for most patients were biphasic or triphasic, although several demonstrated more complex kinetic patterns that suggested significant enterohepatic circulation. The magnitude of the area under the plasma disappearance curve was related to the severity of DCMTX-induced hepatotoxicity. The elimination kinetics were linear, with a mean plasma clearance of 294 mL/min (range, 128-715). The pharmacokinetic behavior of DCMTX does not support its use over methotrexate in regional perfusion. DCMTX's primarily nonrenal elimination suggests that it may have an advantage over methotrexate when combined with nephrotoxic drugs such as cisplatin. However, there is little reason to commit major resources to further evaluation of DCMTX unless significant advantages in antineoplastic activity are identified.

Adult↗
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

Sequential methotrexate and 5-fluorouracil in advanced ovarian carcinoma.

Experimental studies have demonstrated that the combined effects of methotrexate and 5-FU may be optimized in schedules of administration where the antifolate is administered prior to the fluoropyrimidine. Seventeen patients with ovarian carcinoma refractory to standard chemotherapy were treated with a sequence of moderate dose MTX (200 mg/m2) and 5-FU. No responses were seen, although the hematologic and gastrointestinal toxicity which was observed was very mild. Because of prior nephrotoxic chemotherapy and the frequent presence of large amounts of "third space" fluid in the form of malignant ascites, patients with ovarian cancer are at high risk for MTX toxicity. In this study, eight patients with significant ascites had higher plasma MTX concentrations measured at 48 and 72 hr following drug administration than nine similar patients without ascites. This suggested delayed excretion of MTX in patients with ascites although this difference was not statistically significant. MTX concentrations in ascites exceeded those in plasma between 6 and 12 hr and remained near 1 microM for 24 hr. Although the lack of response is disappointing, the modest toxicity encountered with the careful drug level monitoring and the favorable pharmacologic findings suggest that this combination of drugs each with established activity in untreated ovarian cancer deserves further study in primary treatment.

Adult↗
PubMed1987

A phase I study of menogaril in patients with advanced cancer.

Menogaril (7-con-O-methylnogarol) is a semisynthetic anthracycline analogue of nogalamycin that has shown good activity against a variety of experimental tumor systems as well as decreased cardiac toxicity when compared with doxorubicin in preclinical studies. Forty-one patients with refractory solid tumors received menogaril during a phase I trial at The Johns Hopkins Oncology Center (Baltimore). Menogaril was administered as an intravenous (IV) infusion on days 1 and 8 of a 28-day cycle in doses of 8 to 140 mg/m2. Eastern Cooperative Oncology Group (ECOG) grade 3 and 4 leukopenia was the principle dose-limiting toxicity and was occasionally accompanied by thrombocytopenia. Both WBC and platelet nadirs occurred between days 15 and 22. Anemia requiring transfusion was occasionally seen. Nonhematologic toxicities observed included frequent anorexia and malaise that was not dose related and postinfusion phlebitis that was dose related and occasionally dose limiting. Gastrointestinal toxicity and alopecia were infrequent and mild in severity. Three patients with cumulative doses of menogaril greater than 1,400 mg/m2 had no significant changes in ejection fractions as determined by serial gated blood pool scans. Two patients had greater than 10% decrements in ejection fractions without clinical changes at total doses of 128 and 288 mg/m2. One patient with prior anthracycline therapy and chest irradiation decreased her left ventricular ejection fraction from 52% to 30% and developed respiratory failure after two cycles of therapy in the setting of disease progression. No responses to menogaril therapy were observed. The recommended phase II dose for menogaril on this day 1 and 8 schedule is 140 mg/m2. A starting dose of 90 mg/m2 should be considered for heavily pretreated patients. In comparing results of this phase I schedule with those of other schedules, evidence for schedule-dependent toxicity differences should be sought.

Adult↗
PubMed1987

High-performance liquid chromatographic assay for taxol in human plasma and urine and pharmacokinetics in a phase I trial.

Taxol is a unique antineoplastic agent which appears to exert its cytotoxic action as a result of interference with microtubular structure and function. Clinical development of this drug will be facilitated by the availability of sensitive and specific methods for its quantitation in biological fluids. We have developed a reverse-phase high-performance liquid chromatographic assay for taxol capable of detecting concentrations as low as 50 nM, which can be automated using readily available equipment. With this assay we have performed pharmacologic studies of taxol during the conduct of a phase I trial of this compound at The Johns Hopkins Oncology Center. Following a 60- to 360-minute infusion, the plasma disappearance is biexponential, with harmonic mean alpha half-life and beta half-life values of 16.2 minutes and 6.4 hours, respectively. Volumes of distribution for the theoretical central compartment (VDc) and at steady state (VDss) were 8.6 and 67.1 L/m2. Mean plasma clearance was 253 ml/minute/m2. Urinary clearance was 29.3 ml/minute/m2 and 5.9% +/- 8.8% of the drug was identified in 48-hour urine collections. No metabolites have been identified. Over the 18-fold dose range studied, there was no evidence of nonlinearity or dose-dependent behavior. A rough correlation between area under the plasma disappearance curve and hematologic toxicity was observed.

Alkaloids↗
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

Correlation of drug-perturbed marrow cell growth kinetics and intracellular 1-B-D-arabinofuranosylcytosine metabolism with clinical response in adult acute myelogenous leukemia.

To define the relationship between leukemic cell growth, intracellular metabolism of 1-B-D-arabinofuranosylcytosine (ara-C), and the clinical response to timed sequential induction therapy with ara-C in adult acute myelogenous leukemia (AML), growth kinetic and biochemical pharmacologic determinants were examined in AML bone marrow populations. Leukemic blasts from 45 previously untreated patients obtained prior to therapy were cultured in vitro in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). Cell populations cultured in HSA demonstrated both increased proliferation, as measured by both [3H]dThd incorporation into DNA and [3H]dThd leukemic blast labeling index, and greater [3H] ara-C leukemic blast labeling index relative to cells maintained in APS. HSA-cultured marrow cells from the 31 patients who achieved complete remission with ara-C-containing therapy demonstrated enhanced intracellular formation of ara-C 5'-triphosphate over three hours and retention of this active form during one subsequent hour in drug-free medium relative to cells maintained in APS. In contrast, cells from the 14 nonresponsive patients demonstrated no such HSA-induced increases in intracellular ara-C metabolism. These studies of human AML marrow cells identify behavior patterns of ara-C activation and net metabolism in the kinetically perturbed, proliferative state that may discriminate clinical sensitivity from clinical resistance to ara-C-based timed sequential therapy. Sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA-perturbed growth and pharmacologic parameters, while refractory cells demonstrate uncoupling of these determinants in the growth-stimulated state. These in vitro measurements may further serve as a template for prediction of clinical outcome to timed sequential therapy with ara-C, where both pharmacologic and cytokinetic determinants of response are intrinsic to the success of the designed drug scheduling.

Arabinofuranosylcytosine Triphosphate↗
PubMed1987

An in vitro model to predict clinical response in adult acute myelogenous leukemia.

The relationship between in vitro leukemic cell growth kinetics, intracellular biochemical pharmacology of 1-beta-D-arabinofuranosylcytosine (ara-C), and clinical response to ara-C-containing timed sequential therapy was examined in leukemic marrow populations from 62 adults with acute myelogenous leukemia (AML). Leukemic blasts from 45 previously untreated and 17 relapse patients were obtained before therapy, and cultured in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). While all cell populations cultured in HSA demonstrated increased proliferation, only growth-stimulated cohorts from those patients achieving complete remission with ara-C-based therapy demonstrated enhanced intracellular drug activation and active drug retention relative to cells maintained in APS, whereas cells from nonresponsive patients demonstrated no such HSA-induced increases in intracellular ara-C metabolism. In this in vitro model system, sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA-perturbed growth and net pharmacologic parameters, while refractory cohorts evince uncoupling of these determinants in the growth-stimulated state. This model identifies behavior patterns that may discriminate clinical sensitivity from clinical resistance and may serve to predict clinical outcome to timed sequential therapy with ara-C.

Adult↗
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

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↗
PubMed1986

A phase I trial of spirohydantoin mustard (NSC 172112) in patients with advanced cancer.

Spirohydantoin mustard (spiromustine, NSC 172112) is a classical bifunctional alkylating agent synthesized in an effort to develop antitumor agents effective against CNS tumors. The rationale was to combine the reactive moiety of an active antitumor agent with the hydantoin part of the molecule, which might serve as a carrier to cross the blood brain barrier. Thirty-eight patients with refractory solid tumors received spiromustine as part of a phase I trial at the Johns Hopkins Oncology Center. Three schedules were investigated: intravenously (IV) daily for three consecutive days, IV every other day for 3 days, and IV on a weekly basis for three doses, all cycled every 28 days. Hematologic toxicity was infrequently seen. Mild to moderate nausea and vomiting occurred on all schedules. The dose limiting toxicity was CNS toxicity characterized by mydriasis, xerostomia, lethargy, confusion, and hallucinations. This CNS toxicity was dose related, cumulative, and reversible. IV physostigmine appeared to diminish the neurotoxicity if administered before spiromustine and at frequent intervals following the drug. The maximum tolerated dose of spiromustine (without concomitant physostigmine) on the three times a week schedule is 6 mg/m2. With physostigmine pretreatment, 8 mg/m2 can be administered. The three times daily and every other day for three days schedules are not recommended for further study due to the severity of neurotoxicity. It is recommended that 6 mg/m2 be used as the starting dose for any phase II studies using the three times weekly schedule, and that physostigmine be used as needed to minimize neurotoxicity. Dose escalation above this level can be considered when individual tolerance has been established. Phase II trials to investigate the activity of this agent against primary and metastatic CNS malignancies appear indicated on the basis of three transient radiographic responses in refractory malignancies metastatic to the CNS.

Adult↗