ABSTRACT
BACKGROUND: Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. PATIENTS AND METHODS: In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). RESULTS: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients. CONCLUSIONS: The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Azacitidine/analogs & derivatives , Dacarbazine/analogs & derivatives , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/antagonists & inhibitors , Azacitidine/administration & dosage , Azacitidine/adverse effects , Azacitidine/pharmacokinetics , Dacarbazine/administration & dosage , Dacarbazine/pharmacokinetics , Decitabine , Disease-Free Survival , Drug Administration Schedule , Drug-Related Side Effects and Adverse Reactions/chemically induced , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Male , Melanoma/pathology , Middle Aged , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/pathology , Neoplasm Staging , Skin Neoplasms/pathology , TemozolomideABSTRACT
BACKGROUND: Determining the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of sorafenib (S) plus imatinib (IM) in castration-resistant prostate cancer (CRPC) patients. METHODS: Refractory CRPC patients were enrolled onto this 3+3 dose escalation designed study. Imatinib pharmacokinetics (PK) were determined on day 15, 4 h post dose with a validated LC-MS assay. RESULTS: Seventeen patients were enrolled; 10 evaluable (6 at 400 mg S qd with 300 mg IM qd (DL0) and 4 at 400 mg S bid with 300 mg IM qd (DL1)); inevaluable patients received <1 cycle. The median age was 73 (57-89); median prostatic serum antigen was 284 ng ml(-1) (11.7-9027). Median number of prior non-hormonal therapies was 3 (1-12). Dose-limiting toxicities were diarrhoea and hand-foot syndrome. Maximum tolerated dose was 400 mg S and 300 mg IM both daily. No biochemical responses were observed. Two patients had stable disease by RECIST. Median time to progression was 2 months (1-5). Median OS was 6 months (1-30+) with 3/17 patients (17%) alive at 21 months median follow-up. Ten patients had PK data suggesting that S reduced IM clearance by 55%, resulting in 77% increased exposure (P=0.005; compared with historical data). CONCLUSION: This is the first report showing that S+IM can be administered in CRPC at a dose of 400 mg S and 300 mg IM, daily.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzenesulfonates/administration & dosage , Piperazines/administration & dosage , Prostatic Neoplasms/drug therapy , Pyridines/administration & dosage , Pyrimidines/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzamides , Castration , Drug Administration Schedule , Humans , Imatinib Mesylate , Male , Maximum Tolerated Dose , Middle Aged , Niacinamide/analogs & derivatives , Phenylurea Compounds , Piperazines/pharmacokinetics , Pyrimidines/pharmacokinetics , Retreatment , Sorafenib , Treatment FailureABSTRACT
Treatment of maternal chronic myeloid leukemia with imatinib mesylate is avoided because of potential fetal effects. Two women with progression of disease during pregnancy required imatinib therapy. Concentrations of imatinib in maternal blood, placenta, umbilical cord blood and breast milk were 886, 2452, 0 to 157, and 596 ng/ml, respectively. Concentrations of the active metabolite CGP74588 in maternal blood, placenta, umbilical cord blood and breast milk were 338, 1462, 0 and 1513 ng/ml, respectively. As Imatinib and CGP74588 cross the mature placenta poorly, use of the drug after the first trimester may be reasonable under some circumstances. Imatinib and CGP74588 are found in breast milk, and therefore avoidance of breastfeeding is advisable.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/pharmacokinetics , Pregnancy Complications, Neoplastic/drug therapy , Pyrimidines/pharmacokinetics , Antineoplastic Agents/blood , Benzamides , Female , Fetal Blood/metabolism , Humans , Imatinib Mesylate , Milk, Human/metabolism , Piperazines/blood , Piperazines/metabolism , Placenta/metabolism , Pregnancy , Pyrimidines/blood , Pyrimidines/metabolismABSTRACT
Sixteen patients [13 acute nonlymphocytic leukemia (ANLL), 2 acute lymphocytic leukemia, 1 chronic myelogenous leukemia in a blast crisis; median age, 40 yr; range, 25-78 yr; 9 male, 7 female] received 23 courses of carboplatin given as a bolus on a daily X 5 schedule. Six patients were given 7 courses of carboplatin at 200 mg/m2/day; 3 patients received 5 courses at 250 mg/m2; 9 patients received 11 courses at 300 mg/m2; 2 patients initially treated at 200 mg/m2 were given their 2nd course at 300 mg/m2. Significant hearing loss documented by audiometry occurred in five patients, including three of nine treated at 300 mg/m2. All five had prior or recent exposure to aminoglycoside antibiotics. Three patients developed cancer and acute leukemia group B grade 3 or 4 mucositis, and 18 of 23 courses were complicated by nausea and vomiting. Marrows were hypocellular or aplastic in all patients treated at the highest dose. No complete responses occurred, although two patients with ANLL treated at 300 mg/m2 achieved partial responses lasting 71 and 138 days. The t1/2 alpha [half-life (t1/2)], t1/2 beta, and total body clearance of ultrafilterable platinum were comparable to those previously described by us in patients receiving bolus doses of carboplatin of 22-77 mg/m2/day X 5. Carboplatin has activity in ANLL.
Subject(s)
Antineoplastic Agents/adverse effects , Leukemia/drug therapy , Organoplatinum Compounds/adverse effects , Adult , Aged , Antineoplastic Agents/pharmacokinetics , Bone Marrow/drug effects , Carboplatin , Drug Evaluation , Female , Hearing/drug effects , Humans , Kidney/drug effects , Male , Middle Aged , Organoplatinum Compounds/pharmacokineticsABSTRACT
BACKGROUND: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. PURPOSE: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. METHODS: For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 micrograms/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. RESULTS: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts < 100/microL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%-85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. CONCLUSIONS: The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 micrograms/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. IMPLICATIONS: Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.
Subject(s)
Bone Marrow Diseases/prevention & control , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Blood Cell Count/drug effects , Bone Marrow Diseases/chemically induced , Cyclophosphamide/pharmacokinetics , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Neoplasms/metabolismABSTRACT
BACKGROUND: Paclitaxel (Taxol) has been shown to sensitize some malignant cells to the effects of radiation. A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to exploit this phenomenon. The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissue being radiated. Paclitaxel is known to have limited access to the central nervous system (CNS) of rats and mice, but its ability to penetrate malignant tissue in the CNS is inadequately documented. PURPOSE: Our purpose was to examine the concentrations of paclitaxel in the cerebrospinal fluid (CSF) of patients with CNS malignancies and in normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concomitant paclitaxel concentrations in the plasma of those same patients and animals. METHODS: Four patients were treated with 3-hour infusions of paclitaxel at doses between 90 and 200 mg/m2. Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of the paclitaxel infusion. Four Fischer rats had 20,000 C6 glioma cells stereotactically implanted into their right frontal lobes; 28 days later, they were given 3-hour infusions of paclitaxel at 10 mg/kg. Plasma was sampled during the paclitaxel infusion. At the completion of the infusion, rats were killed, and portions of their normal and malignant CNS tissues were removed for histologic assessment. Concentrations of paclitaxel in plasma, CSF, and brain tissue were determined with high-pressure liquid chromatography. RESULTS: Plasma pharmacokinetics of paclitaxel in patients with brain tumors were comparable to those previously described in patients with other malignancies. Paclitaxel could be measured in CSF of all patients, but concentrations were very low. Peak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occurred between 3.25 and 5 hours after initiation of the paclitaxel infusion. Peak paclitaxel concentrations in CSF were between 0.12% and 8.3% of those present in concomitant plasma samples. Paclitaxel was not detectable in the normal or malignant CNS tissue of any rat, despite the fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 microM. CONCLUSIONS: Paclitaxel has only limited access to the CSF of patients with CNS malignancies and to normal and malignant CNS tissues of rats bearing brain tumors. IMPLICATIONS: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.
Subject(s)
Brain Neoplasms/blood , Brain Neoplasms/cerebrospinal fluid , Brain/metabolism , Paclitaxel/pharmacokinetics , Adult , Aged , Animals , Female , Glioma/blood , Glioma/cerebrospinal fluid , Humans , Infusions, Intravenous , Middle Aged , Paclitaxel/administration & dosage , Rats , Rats, Inbred F344ABSTRACT
BACKGROUND: Previous studies indicate that suramin may be an active agent for treatment of solid tumors. The clinical use of suramin is complicated by a broad spectrum of toxic effects and complex pharmacology. Studies have suggested that the dose-limiting neurotoxicity of this agent is closely related to sustained plasma drug concentrations of 350 micrograms/mL or more. PURPOSE: This phase I clinical trial in patients with solid tumors was designed to determine whether plasma concentrations resulting in both antitumor activity and manageable toxicity could be achieved with short, intermittent infusions of suramin. METHODS: Thirty-seven patients, including 33 with metastatic, hormone-refractory prostate cancer, collectively received 43 courses of suramin designed to maintain a plasma concentration range of 200-300, 175-275, or 150-250 micrograms/mL. Patients received a test dose of 200 mg and an initial loading dose of 1000 mg/m2 on day 1 of therapy. Subsequent suramin doses and schedules were individually determined using a strategy of adaptive control with feedback, which used a maximum a posteriori Bayesian algorithm to estimate individual pharmacokinetic parameters. Patients were treated until dose-limiting toxicity or progressive disease developed. RESULTS: Thirty-five of the 37 study patients and 31 of the 33 with prostate cancer were assessable for toxicity and response. Treatment was discontinued in 28 patients because of dose-limiting toxicity consisting of a syndrome of malaise, fatigue, and lethargy; recurrent reduction in creatinine clearance of 50% or more; or axonal neuropathy. Evidence of major antitumor activity was observed in patients with prostate cancer treated at all three plasma drug concentrations. Measurable responses (one complete response and five partial responses) were noted in six of 12 patients with measurable disease. Twenty-four (77%) of 31 patients had a reduction in prostate-specific antigen of 50% or more, and 17 (55%) of 31 had a reduction of 75% or more. Twenty (83%) of 24 patients reported reduction in pain. CONCLUSIONS: Suramin can be safely administered as an intermittent bolus injection by use of adaptive control with feedback to control plasma drug concentrations; toxicity is significant but manageable and reversible. Suramin is active against hormone-refractory prostate cancer. IMPLICATIONS: Future trials should address the role and necessary extent of therapeutic drug monitoring; the optimal plasma drug concentration range and duration of therapy; and the activity of suramin in combination with other agents, in earlier stages of prostate cancer, and in other tumor types.
Subject(s)
Antineoplastic Agents/therapeutic use , Prostatic Neoplasms/drug therapy , Suramin/therapeutic use , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Drug Administration Schedule , Humans , Infusions, Intravenous , Male , Middle Aged , Prostatic Neoplasms/blood , Prostatic Neoplasms/pathology , Suramin/adverse effects , Suramin/pharmacokinetics , Treatment OutcomeABSTRACT
N,N',N''-Triethylenethiophosphoramide ([14C]thiotepa) accumulation by L1210 cells is a biphasic process. A very rapid initial phase is followed by a much slower second phase that reflects accumulation of radioactivity in a form that is not lost or exchanged when cells are resuspended and incubated in drug-free medium for up to 8 h. In this study we attempted to characterize this nonexchangeable radioactivity. Nuclei (10(7)) isolated from L1210 cells and incubated with [14C]thiotepa did not accumulate 14C during incubations of up to 5 h. Similarly, nuclei isolated from 10(7) L1210 cells that had been shown to accumulate nonexchangeable 14C after incubation with [14C]thiotepa did not show an increase in nuclear-associated 14C. Eighty to 85% of nonexchangeable 14C in L1210 cells incubated with [14C]thiotepa was soluble in ethanol or chloroform:methanol (2:1, v/v), and although most of this cell-associated nonexchangeable 14C was precipitated by trichloroacetic acid, subsequent treatment of that precipitate with methanol solubilized most of the 14C so that only 15 to 20% remained with the final precipitate. When chloroform:methanol-soluble nonexchangeable 14C was analyzed with thin-layer chromatography systems suitable for thiotepa or simple lipids, all radioactivity remained at the origin. In contrast, when analyzed with one- and two-dimensional thin-layer chromatographic systems suitable for complex lipids, all chloroform:methanol-soluble radioactivity was associated with a single lipid spot. This lipid cochromatographed with phosphatidylethanolamine, reacted with ninhydrin but not with 4-(p-nitrobenzyl)pyridine or the Dragendorff choline reagent, and was digested by phospholipases C and D, all of which lead to its identification as phosphatidylethanolamine. This extensive labeling of phosphatidylethanolamine in L1210 cells incubated with [14C]thiotepa can be explained by liberation of [14C]aziridine from [14C]thiotepa, hydrolysis of the [14C]aziridine to [14C]ethanolamine, and incorporation of that radiolabeled material into phosphatidylethanolamine via the normal cellular synthetic pathways for that lipid. This information implies that thiotepa serves, at least in part, as a prodrug for aziridine and has implications as to the mechanism of thiotepa-induced cytotoxicity in that aziridine is a monofunctional alkylating agent incapable of producing interstrand, intrastrand, or protein-DNA cross-links.
Subject(s)
Leukemia L1210/metabolism , Phosphatidylethanolamines/metabolism , Thiotepa/pharmacokinetics , Animals , Carbon Radioisotopes/analysis , Cell Nucleus/metabolism , Chromatography, Thin Layer , Time FactorsABSTRACT
The amino alcohols, ethanolamine and choline, were studied for their effects on (a) L1210 cell growth, (b) N,N',N"-triethylenetheiphosphoramide (thiotepa)-induced growth inhibition of L1210 cells, and (c) 14C accumulation by L1210 cells incubated with [14C]thiotepa. Ethanolamine, at concentrations up to 300 microM, had no effect on L1210 cell growth but, at concentrations greater than 300 microM, produced a dose-dependent reduction in cell growth. Choline, at concentrations up to 20 mM, had no effect on L1210 cell growth. Neither ethanolamine, at 250 microM, nor choline, at 10 mM, altered the ability of thiotepa to reduce L1210 cell growth. Neither ethanolamine, at 250 microM, nor choline, at 10 mM, affected the rapid phase of 14C accumulation by L1210 cells incubated with [14C]thiotepa. The slow phase of 14C accumulation by L1210 cells incubated with 5 microM [14C]thiotepa, a process which is 80-85% due to production of [14C]phosphatidylethanolamine, was not affected by 250 microM choline. In contrast, ethanolamine produced a dose-dependent reduction in this slow rate of 14C accumulation. The reduction in the slow rate of 14C accumulation produced by ethanolamine was due almost entirely to a decrease in the accumulation of nonexchangeable 14C. Kinetic analysis of the inhibition of 14C accumulation produced by 25, 100, and 250 microM ethanolamine was compatible with competitive inhibition. Thin layer chromatography of cell extracts showed that the ability of ethanolamine to reduce 14C accumulation by L1210 cells incubated with [14C]thiotepa was due solely to reduction in production of [14C]phosphatidylethanolamine. These results are all compatible with and predicted by our previously described scheme wherein thiotepa enters cells by simple diffusion and serves as a prodrug for aziridine, some of which is hydrolyzed to ethanolamine which is then incorporated into phosphatidylethanolamine via normal metabolic synthetic pathways.
Subject(s)
Choline/pharmacology , Ethanolamines/pharmacology , Leukemia L1210/metabolism , Thiotepa/metabolism , Tumor Cells, Cultured/metabolism , Animals , Carbon Radioisotopes , Cell Survival/drug effects , Ethanolamine , Kinetics , Mice , Radioisotope Dilution Technique , Thiotepa/pharmacology , Tumor Cells, Cultured/cytology , Tumor Cells, Cultured/drug effectsABSTRACT
Hexamethylene bisacetamide, a compound which in vitro induces differentiation in a wide variety of human and animal cancer cell lines, is being investigated in phase I clinical trials. After i.v. administration of hexamethylene bisacetamide to humans, urine contained the parent compound and at least five metabolites formed by deacetylation and oxidation pathways. Identification of urinary metabolites was accomplished by gas chromatography-mass spectrometric analysis after isolation by ion exchange chromatography or extraction with ethyl acetate. Metabolites with amino or alcohol groups were trifluoroacetylated and acidic functional groups were esterified with 2,2,2-trifluoroethanol or methanol. The structure of each metabolite was confirmed by comparison with authentic standards. Metabolites identified included the major metabolite, 6-acetamidohexanoic acid; the monodeacetylated product, N-acetyl-1,6-diaminohexane; the bis-deacetylated diamine, 1,6-diaminohexane; and the amino acid, 6-aminohexanoic acid and its lactam, caprolactam.
Subject(s)
Acetamides/metabolism , Cell Differentiation/drug effects , Acetamides/pharmacology , Biotransformation , Gas Chromatography-Mass Spectrometry , HumansABSTRACT
Because the transport and accumulation of thiotepa by cells has not been characterized, these process were investigated with [14C]thiotepa and cultured L1210 or freshly obtained human or avian RBC. The octanol:phosphate buffered saline partition coefficient of thiotepa was 2.4 +/- 0.1 (n = 8). With this value, the permeability coefficient (P) for thiotepa was estimated to be between 2.8 X 10(-4) and 1.81 X 10(-3) cm/s and the half-life of accumulation of thiotepa by L1210 cells was estimated to be 0.063-0.40 s. Thiotepa accumulation by cells was measured after incubation of cell with [14C]thiotepa and subsequent harvesting of cells by centrifugation through silicone fluid. Thiotepa accumulation by L1210 cells was biphasic. The initial phase was rapid essentially complete by 10 s. The amount of cell-associated 14C increased linearly with increasing extracellular concentrations of thiotepa or with increasing size of the cell pellet. The absolute amount of cell-associated 14C was consistent with that expected if the [14C]thiotepa had been evenly distributed in the incubation medium and a volume equal to that of the cell pellet had been sampled and counted. This rapid phase of thiotepa accumulation was not slowed when cells were incubated on ice. The second phase of [14C]thiotepa accumulation occurred at a rate much slower than that of the initial phase. This slower phase of drug accumulation was linear for at least 5 h. The rate of 14C accumulation increased progressively over a range of extracellular thiotepa concentrations between 5 and 100 nmol/ml and could not be saturated under acceptable tissue culture conditions. The slower rate of 14C accumulation was ablated by incubation cells on ice and was reduced by 30-50% in the presence of 1 mM sodium azide or 2,4-dinitrophenol. The slow rate of accumulation of 14C reflected summation of a relatively stable or constant amount of exchangeable 14C an an amount of nonexchangeable 14C which increased linearly from almost undetectable levels at the start of the experiment to amounts approximately equal to those of exchangeable radioactivity after 5 h. The initial association of [14C]thiotepa with both human and avian RBCs was also very rapid. Avian RBCs also exhibited a slow rate of 14C accumulation which was linear for at least 5 h which was 15-20% that of L1210 cells. Human RBCs did not exhibit a slower rate of 14C accumulation and essentially all of the 14C associated with human RBCs was exchangeable for the 5 h duration of the experiment.(ABSTRACT TRUNCATED AT 400 WORDS)
Subject(s)
Thiotepa/metabolism , Animals , Biological Transport , Biotransformation , Cell Membrane Permeability , Humans , Kinetics , Leukemia L1210/metabolism , Mice , Temperature , Tumor Cells, CulturedABSTRACT
We have investigated the metabolism and disposition, in rabbits, of menogaril (7-OMEN), a new anthracycline antibiotic recently introduced into clinical trials. 7-OMEN was administered by rapid i.v. injection at a dosage of 2.5 mg/kg. 7-OMEN and metabolites were assayed by high performance liquid chromatography. Plasma concentrations of 7-OMEN declined in biexponential fashion with a terminal half-life of 2.7 h. The area under the plasma concentration versus time curve was 1.3 microM X h. The systemic clearance of 7-OMEN was 57.6 ml/min/kg. No metabolite of 7-OMEN was detected in plasma. At 8 h after treatment, the cumulative urinary and biliary excretions of 7-OMEN equivalents amounted to 1.3 and 3.4% of the total administered dose, respectively. 7-OMEN was the predominant fluorescent compound in urine, but four metabolites were also seen. In bile, 7-OMEN represented only 9.6% of the cumulative excretion and six metabolites were observed. Among the organs, lungs contained the highest concentrations of parent drug. Substantial concentrations of metabolites were observed in the kidneys, liver, duodenum, and small intestine. Three of the observed metabolites of 7-OMEN have been tentatively identified as N-demethylmenogaril, 7-deoxynogarol, and N-demethyl-7-deoxynogarol.
Subject(s)
Antineoplastic Agents/metabolism , Daunorubicin/analogs & derivatives , Nogalamycin/metabolism , Animals , Bile/metabolism , Fluorescence , Male , Menogaril , Metabolic Clearance Rate , Nogalamycin/analogs & derivatives , Rabbits , Tissue DistributionABSTRACT
N,N',N"-Triethylenethiophosphoramide (thiotepa) was dissolved at 100 micrograms/ml in urine or in 0.1 M sodium acetate buffer and incubated at 37 degrees or 22 degrees. After 0, 15, 30, 60, 90, and 120 min of incubation, 0.1-ml samples were extracted into ethyl acetate and analyzed by gas-liquid chromatography (1.8-m X 2-mm column packed with 3% OV225 on 100/120 Supelcoport; oven at 180 degrees; injection port and nitrogen-phosphorus detector at 230 degrees). Thiotepa was more stable at 22 degrees than at 37 degrees and at pH 6 to 7 than at pH 4 to 5.5. After 2 hr of incubation at 37 degrees, thiotepa concentrations decreased by 40% at pH 5.0 but only 10% at pH 6 or 7. Although thiotepa concentrations declined as described above, alkylating activity, as assessed by p-nitrobenzyl pyridine reactivity, was stable at all temperatures and pHs tested. Partition coefficients of thiotepa degradation products into toluene, ethyl acetate, diethyl ether, and hexane were determined after 0 and 120 min of incubation in urine at pH 4.0. The extractability of alkylating activity into these organic solvents decreased dramatically after 120 min. Thiotepa degradation products were extracted from urine at pH 4.0 after 0, 30, 60, and 120 min incubation at 37 degrees and were separated by thin-layer chromatography. In addition to thiotepa (Rf 0.15), 3 degradation products possessing p-nitrobenzyl pyridine alkylating activity (Rf 0.35, 0.52, and 0.60) were observed during the course of incubation. The structures of the materials with Rf 0.35 and 0.52 were identified by mass spectrometry and indicated that thiotepa degradation occurs by successive addition of HCl molecules with opening of the aziridine rings and conversion to 2-chloroethyl moieties.
Subject(s)
Thiotepa/urine , Buffers , Chromatography, Gas , Chromatography, Thin Layer , Drug Stability , Humans , Hydrogen-Ion Concentration , Kinetics , Mass Spectrometry , TemperatureABSTRACT
The cellular accumulation and disposition of the anthracycline antitumor antibiotic aclacinomycin A (ACM) were compared to those of daunorubicin. Although both drugs were avidly accumulated by cells, intracellular concentrations of ACM were two to three times those of daunorubicin. Whereas lowered temperature (0 degrees) reduced intracellular accumulation of both drugs, 10 mM sodium azide had no effect on accumulation of either ACM or daunorubicin. Both drugs exited from cells placed in drug-free medium, a process that was reduced at 0 degrees but not altered by 10 mM sodium azide. Unlike whole cells, isolated nuclei accumulated more daunorubicin than ACM. This process was not altered at 0 degrees. Both drugs were lost from nuclei placed in drug-free buffer, a process that was reduced at 0 degrees. Unlike daunorubicin, which localized in cell nuclei, ACM localized in the cytoplasm with no detectable nuclear fluorescence. Although both drugs produced dose-dependent inhibitions of [3H]thymidine and [3H]uridine incorporation by L1210 and P388 cells, ACM inhibited both processes at lower concentrations than did daunorubicin. While daunorubicin inhibited [3H]thymidine incorporation more effectively than [3H]uridine incorporation, the reverse was observed with ACM.
Subject(s)
Antibiotics, Antineoplastic/metabolism , Leukemia L1210/metabolism , Leukemia P388/metabolism , Leukemia, Experimental/metabolism , Animals , Antibiotics, Antineoplastic/pharmacology , Cell Line , Cell Nucleus/metabolism , Cytoplasm/metabolism , Daunorubicin/metabolism , Daunorubicin/pharmacology , Mice , Naphthacenes/metabolism , Naphthacenes/pharmacology , Nucleic Acids/biosynthesisABSTRACT
We investigated whether leukemic cell lines could convert hexamethylene bisacetamide (HMBA) to any of the metabolites previously identified and quantified in the urine and plasma of patients treated with HMBA. After 5-7 days of incubation with 1-2 mM HMBA, HL60 human promyelocytic leukemic cells, L1210 and P388 murine lymphoblastic leukemic cells, and Friend murine erythroleukemia cells contained 4 of the previously identified metabolites of HMBA. Gas chromatography/mass spectrometry confirmed the presence of N-acetyl-1,6-diaminohexane (NADAH), 1,6-diaminohexane (DAH), 6-acetamidohexanoic acid (AcHA), and 6-aminohexanoic acid (AmHA). Gas chromatography with nitrogen-phosphorus selective detection was used to quantify cellular concentrations of each metabolite. Cellular concentrations of AmHA and DAH were greater than those of NADAH and AcHA but no concentration of a metabolite exceeded that of HMBA. Metabolites were not detected in media from cells incubated with HMBA. Friend murine erythroleukemia cells that were resistant to HMBA contained only HMBA and NADAH. Moreover, the concentrations of NADAH in Friend murine erythroleukemia cells that were resistant to HMBA were less than those in the other cell lines studied. HL60 cells accumulated HMBA rapidly. NADAH, DAH, AcHA, and AmHA appeared sequentially in HL60 cells that were incubated with HMBA. NADAH appeared very rapidly, but concentrations of DAH were greater than or equal to those of NADAH by 8 h. AcHA and AmHA were not detected in cells before 24-48 h of incubation with HMBA. HL60 cells incubated with individual HMBA metabolites were able to accumulate each compound and to interconvert some: cells incubated with NADAH also contained DAH, AcHA, and AmHA; cells incubated with AcHA also contained low concentrations of AmHA; cells incubated with DAH also contained AmHA; and cells incubated with AmHA contained no other HMBA metabolites. HMBA was not present in cells incubated with any of its known metabolites. These results document the ability of various leukemic cells to metabolize HMBA, indicate the unidirectional catabolism of that compound, and may have implications as to its mechanism of action.
Subject(s)
Acetamides/metabolism , Leukemia, Experimental/metabolism , Animals , Humans , Leukemia L1210/metabolism , Leukemia P388/metabolism , Leukemia, Myeloid, Acute/metabolism , Mice , Tumor Cells, CulturedABSTRACT
We studied the ability of five metabolites of hexamethylene bisacetamide (HMBA), which we had previously identified in patient urine, to induce differentiation or to influence differentiation induced by HMBA of a human promyelocytic cell line. Differentiation of HL60 cells was quantified by morphological changes and by the ability to reduce nitroblue tetrazolium. N-Acetyl-1,6-diaminohexane (NADAH), the deacetylated, first metabolite of HMBA, was a more potent inducer of HL60 differentiation than was HMBA. NADAH produced 20-30% differentiation at 0.25 mM and 30-40% differentiation at 0.5 mM. NADAH (1 mM) induced 2-3-fold more differentiation than did 1 mM HMBA. HL60 differentiation, induced by various combinations of HMBA and NADAH, reflected a combined effect of the two compounds. In contrast, 1,6-diaminohexane, at 0.5-5 mM, failed to induce HL60 differentiation. Similarly, 0.5-5 mM 6-acetamidohexanoic acid, the major metabolite of HMBA, and 6-aminohexanoic acid failed to induce differentiation of HL60 cells. However, 6-acetamidohexanoic acid, when combined with HMBA or NADAH at various concentrations and ratios, enhanced the differentiation of HL60 cells induced by these two compounds. This enhancement was most apparent with addition of 0.50-3.0 mM 6-acetamidohexanoic acid to HL60 cells incubated with 1.0-3.0 mM HMBA or 0.25-1.0 mM NADAH. 6-Aminohexanoic acid similarly enhanced HMBA-induced differentiation of HL60 cells. These in vitro results have implications in terms of the clinical application of HMBA and interpretation of the results of clinical trials performed to date and may provide some insight into the mechanism of HMBA-induced cellular differentiation.
Subject(s)
Acetamides/pharmacology , Cell Differentiation/drug effects , Leukemia, Myeloid, Acute/pathology , Dose-Response Relationship, Drug , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
We previously correlated both renal function and thrombocytopenia, the dose limiting toxicity of carboplatin, with the plasma pharmacokinetics of carboplatin. From these correlations, we developed equations to calculate carboplatin dosage for any patient based on that patient's creatinine clearance, body surface area, pretreatment platelet count, desired platelet nadir, and status of prior chemotherapy. We prospectively applied these equations in 44 courses of carboplatin given to 24 patients. There were 13 males and 11 females with median age 53 (range, 33-77), median Karnofsky performance status 80 (range, 50-100), and creatinine clearance 32 to 118 ml/min. Ten patients had creatinine clearances less than 60 ml/min. Precision of the equations used for dose calculation was evaluable in 38 courses administered to 23 patients. In 23 courses of carboplatin administered to 12 patients without extensive prior chemotherapy, the observed change in platelets = 1.04 X predicted change -48,000 (r = 0.96). In the 15 courses of carboplatin administered to 11 heavily pretreated patients, the observed change in platelets = 1.13 X predicted change +6,600 (r = 0.97). For the overall combined population, the observed change in platelets = 0.96 X predicted change -7,000 (r = 0.94). These relationships which nearly define the line of identity (observed = expected) validate our initial observations. Only 2 patients developed WBC less than 2,000, but 12 patients developed hematocrit less than or equal to 29% and 8 required RBC transfusions. Fifteen patients had nausea and vomiting greater than or equal to grade 2. There were no other nonhematological toxicities observed. In view of continuing documentation of the antitumor activity of carboplatin, these equations allow safe and rational drug dosing of patients with potentially platinum-responsive tumors but with renal function too poor to receive cisplatin. Among the 9 patients in this study evaluable for response, there was 1 partial response in a patient with malignant melanoma and 1 objective response (less than partial response) in a patient with adenocarcinoma of the cervix.
Subject(s)
Organoplatinum Compounds/administration & dosage , Blood Cell Count , Blood Platelets/drug effects , Carboplatin , Humans , Kidney Function Tests , Nausea/chemically induced , Organoplatinum Compounds/adverse effectsABSTRACT
Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was administered to patients with refractory malignant tumors. Thirteen patients received 30 evaluable courses. HMBA was given by continuous i.v. infusion for 5 days. Therapy was repeated every 28 days, if patients had recovered from toxicity. The starting dose was 24 g/m2/day. Because our previous trial had shown wide interpatient variability in HMBA pharmacokinetics and excess toxicity at HMBA plasma concentrations greater than 2 mM (HMBA doses between 24 and 33.6 g/m2/day), we attempted to individualize each patient's dose based on a dosing scheme using an adaptive (feedback) control algorithm, which assumed linear clearance for HMBA. In all courses, a plasma sample was assayed daily and infusion rates were adjusted to achieve an HMBA plasma concentration of 1.5-2.0 mM (300-400 mg/liter). The patients included 12 men and 1 woman with a median age of 56 years (range, 34-76) and median Karnofsky performance status of 90% (range, 60-100). All patients had received prior chemotherapy and 9 patients had also received radiation therapy. The linear adaptive control algorithm was reasonably precise, with a mean absolute error of 0.28 (SE 0.04) mM. However, adjustments in infusion rate systematically overshot the desired change in steady state concentration, probably due to nonlinear clearance of HMBA. For levels within 24 h of a change in infusion rate, this resulted in significant bias, with a mean error of 0.24 (SE 0.09) mM. The mean absolute error was 0.40 (SE 0.06) mM. A second adaptive control algorithm, using a pharmacokinetic model with parallel first-order (renal) clearance and Michaelis-Menten (nonrenal) clearance and using Bayesian parameter estimation with a priori estimates based on our previous phase I trial, proved to be much more precise than the linear method and was unbiased when applied retrospectively to the same observations, with a mean error (within 24 h of a change in infusion rate) of 0.02 (SE 0.06) mM and a mean absolute error of 0.22 (SE 0.03) mM. Toxicity was reversible in all cases. Neurotoxicity, consisting of hallucinations, agitation, somnolence, or confusion, was seen in 2 patients. Four patients complained of insomnia or anxiety. Mild asymptomatic acidosis was seen in 3 patients. Other toxicity included grade 1-2 nausea and vomiting (10 patients), grade 2 diarrhea (2 patients), grade 3 thrombocytopenia (3 patients), grade 1-3 leukopenia (3 patients), and oral herpes simplex infection (4 patients). Mild reversible renal insufficiency (measured by creatinine clearance) was seen in 8 patients.(ABSTRACT TRUNCATED AT 400 WORDS)
Subject(s)
Acetamides/toxicity , Antineoplastic Agents/toxicity , Neoplasms/drug therapy , Acetamides/pharmacokinetics , Acetamides/therapeutic use , Algorithms , Drug Evaluation , Humans , Thrombocytopenia/chemically inducedABSTRACT
Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was tested in patients with refractory, solid tumors. Twenty patients received 25 evaluable courses. HMBA was given by continuous i.v. infusion for 5 consecutive days with courses repeated every 4 wk, provided there was acceptable, reversible toxicity. The starting dose was 4.8 g/m2/day for 5 days with escalations in subsequent cohorts of patients to 43.2 g/m2/day for 5 days. The patients included 12 females and eight males with median age of 56 yr (range 35 to 75 yr) and a median performance status of 80% (range, 60 to 100%). All except two patients had received prior chemotherapy, radiation therapy, or both. Metabolic acidosis and neurotoxicity, consisting of agitation, hallucinations, confusion, and alteration of consciousness, were dose dependent and dose limiting. The one patient treated with 43.2 m/m2/day became acidotic, agitated, and disoriented but recovered to his previous mental and electrolyte status by 8 days after the end of the HMBA infusion. One patient treated with 33.6 g/m2/day became severely acidotic (pH 7.07) and obtunded and also developed myocardial and cerebral infarctions during the HMBA infusion. The other two patients treated with 33.6 g/m2/day became mildly agitated during drug infusion. Six patients were treated at 24 g/m2/day without neurotoxicity. Transient renal insufficiency was seen in the two patients with severe neurotoxicity and in three other patients. Dose-related, mild to moderate nausea and vomiting were observed in ten patients. Four patients developed cutaneous herpes infections during treatment. White blood cell depression was not dose related, and at 24 g/m2/day, the median white blood cell nadir was 4,500/microliter (range, 2,000 to 7,900/microliter). Thrombocytopenia was dose related. At 24 g/m2/day, the median platelet count nadir was 207,000/microliter (range, 66,000 to 542,000/microliter). No objective tumor regressions were noted. HMBA pharmacokinetics was studied at all dosages. Plasma and urine samples from 20 patients were analyzed by gas-liquid chromatography for parent compound. HMBA plasma steady-state concentrations (Css) were achieved in all patients by 12 to 24 h into infusion. Once Css was achieved, daily variation was generally less than or equal to 10% from the mean Css. HMBA plasma Css increased linearly with dose, but there was variation in the Css achieved in individual patients at each dose. Doses of 24 to 33.6 g/m2/day consistently produced plasma HMBA Css of 1 to 2 mM matching concentrations required for differentiation in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)
Subject(s)
Acetamides/administration & dosage , Neoplasms/drug therapy , Acetamides/adverse effects , Acetamides/metabolism , Acidosis/chemically induced , Drug Administration Schedule , Drug Evaluation , Hematopoiesis/drug effects , Humans , Kidney/drug effects , Kinetics , Metabolic Clearance Rate , Nausea/chemically induced , Nervous System/drug effectsABSTRACT
We performed a phase I study of menogaril to determine if dosage reduction was required in patients with hepatic dysfunction and if the relationship between pharmacokinetics and leukopenia, previously defined in patients with normal hepatic and renal function, was altered. Eighteen patients received 27 courses of menogaril, of which 26 were evaluable for toxicity. Patient characteristics were median age, 63 years (range, 28-80 years), 14 male/4 female, and median Karnofsky performance status 80% (range, 60-100%). Prior therapy included none, five; chemotherapy only, seven; radiotherapy only, two; and chemotherapy and radiotherapy, four. Menogaril was administered as a 2-h.i.v. infusion every 28 days at 62.5 (one patient), 125 (eight patients), 187.5 (seven patients), and 250 mg/m2 (six patients), based on pretreatment serum bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Patients also had indocyanine green and antipyrine clearances measured before menogaril treatment. Menogaril and metabolites were assayed by high performance liquid chromatography. Dose-limiting toxicity was leukopenia. WBC nadirs occurred between days 8 and 20 (median, 15). Three patients developed platelet nadirs below 100,000/microliters. Other toxicities included grade I nausea and vomiting in three patients and phlebitis at the site of drug infusion in six patients. Correlations were defined between pretreatment indocyanine green clearance and serum concentrations of alkaline phosphatase and total bilirubin. There were no correlations between pretreatment serum concentrations of bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, indocyanine green clearance or antipyrine and menogaril clearances. Menogaril pharmacokinetics in patients with elevated liver function tests was indistinguishable from that described in patients with normal liver function tests. There were excellent correlations between plasma area under the curve of menogaril and the percentage decreases in WBC and neutrophils. These were well described by two models previously used to study the same relationships in patients with normal hepatic and renal function. When compared to previous studies, patients with hepatic and renal dysfunction had a greater percentage decrease in WBC for any given area under the curve than did patients with normal hepatic and renal function. On the other hand, there was no difference in the relationship between percentage decrease in neutrophils and menogaril area under the curve in these two groups of patients.(ABSTRACT TRUNCATED AT 400 WORDS)