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1.
Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics 总被引:1,自引:0,他引:1
B. A. Conley Merrill J. Egorin Rajeshwari Sridhara Rebecca Finley Ramzi Hemady Suhlan Wu Nancy S. Tait David A. Van Echo David A. Van Echo 《Cancer chemotherapy and pharmacology》1997,39(4):291-299
A phase I trial of all-trans-retinoic acid (ATRA) was conducted to establish the maximum tolerable dose (MTD) of ATRA given
once daily to patients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA
once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA were assessed on day
1 for all patients and weekly for 31 patients who received doses of ≥110 mg/m2 per day. Patients were followed for toxicity and response. Correlations of toxicity frequency and grade with pharmacokinetic
parameters were sought. In addition, correlation of changes in ATRA pharmacokinetics with the concentration of ATRA metabolites
in plasma were sought. A total of 49 patients received ATRA at doses ranging from 45 to 309 mg/m2 per day. Hypertriglyceridemia was dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous dryness and headache. With chronic dosing, plasma ATRA concentrations
fell in 59% of patients. Stable, low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients respectively. Age, gender,
smoking, or concurrent medication did not correlate with the pharmacokinetic pattern. Severe toxicities tended to occur with
initial peak [ATRA] of ≥0.5 μg/ml (1.7 μM), and the toxicity frequency did not change if [ATRA] decreased with continued dosing. No consistent change in 4-oxo-ATRA
or retinoid glucuronide concentrations was observed with decreases in plasma [ATRA]. The recommended once-daily ATRA dose
is 215 mg/m2, although significant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically
significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other
factors, such as responses at target tissues, may be at least as important as the plasma ATRA concentration in predicting
toxicity and/or response.
Received: 7 January 1996 / Accepted: 24 June 1996 相似文献
2.
Purpose: Often the best method of integrating chemotherapeutic agents is unknown. Recently there has been interest in the use of combinations
of the topoisomerase II inhibitors and the topoisomerase I inhibitors as these agents have shown individual activity in malignancies
such as non-small-cell lung cancer. This study examined the interaction of the topoisomerase II inhibitor etoposide with the
topoisomerase I inhibitor topotecan (Tpt) in V79 cells (hamster lung fibroblast cells) to determine the optimal method of
delivering these agents. Methods and results: Cell survival was assessed by colony formation. Synergistic interactions were assessed by the median effect principle in
which a combination index (CI) of less than one suggests a synergistic interaction. The V79 cells were exposed to sequential
24-h incubations with the two chemotherapeutic agents. Initially, equitoxic doses of the two agents were delivered (i.e. 0.0275 μg/ml
of topotecan alone or 0.089 μg/ml of etoposide alone resulting in a surviving fraction of 70%; Tpt : etoposide ratio 1 : 3.2).
It was determined that a sequence-dependent synergistic interaction (CI<1) resulted at a lower level of cytotoxicity if the
etoposide exposure followed the Tpt exposure compared to the opposite sequence. This same effect was seen after treatment
of cells with various concentration (μg/ml) ratios of Tpt : etoposide (1 : 4.0, 1 : 1, 2.5 : 1). Conclusions: These results suggest that maximum synergy occurs for the delivery of etoposide following Tpt exposure (compared to the opposite
sequence) and these findings may have important clinical implications.
Received: 29 September 1995/Accepted: 25 March 1996 相似文献
3.
A. A. Khan Judith G. Villablanca C. Patrick Reynolds Vassilios I. Avramis 《Cancer chemotherapy and pharmacology》1996,39(1-2):34-41
A phase I clinical trial of 13-cis-retinoic acid (cis-RA) was undertaken to determine the maximally tolerated dose (MTD) and pharmacokinetics (PK) of cis-RA following bone marrow transplantation (BMT) in children with high-risk neuroblastoma. Mean peak serum levels of cis-RA in 31 pediatric patients ranged from 4.9 to 8.9 μM following doses of 100–200 mg/m2 per day, divided into two doses every 12 h administered orally. The PK of cis-RA obeyed a single-compartment model following first-order absorption in the majority of patients. A linear increase in the
mean peak serum levels and area under the time-concentration curve (AUC) with increasing dose was observed. The average half-lives
of absorption and elimination were 1.0 and 5.8 h, respectively. At the MTD of 160 mg/m2 per day, the mean cis-RA peak serum concentration was 7.2±5.3 μM. AUC values were not altered significantly during a 2-week course of treatment or over a long period of multiple courses.
Levels of trans-retinoic acid, a metabolite of cis-RA, remained low but were similar on days 1 and 14, whereas the 4-oxo-13-cis-RA metabolite had increased in 64% of patients by day 14. Peak serum cis-RA concentrations correlated with clinical toxicity as grade 3 to 4 toxicity was seen in 44% of patient-courses (8/18) with
peak serum levels ≥10 μM, but only 13% (12/96) with peak serum levels <10 μM. These results show that cis-RA given at 160 mg/m2 to children achieved serum concentrations known to be effective against neuroblastoma in vitro, and the PK for cis-RA differs from that reported for trans-retinoic acid in children.
Received: 6 February/Accepted: 29 January 1996 相似文献
4.
F. Robert Shande Chen Antonius A. Miller Beverly C. Lee David C. Molthrop Richard H. Wheeler 《Cancer chemotherapy and pharmacology》1996,38(5):459-465
Purpose. This phase I study was undertaken to evaluate the safety and tolerability of prolonged infusional etoposide, and to evaluate
its pharmacokinetic/pharmacodynamic profile in patients with advanced cancer. Methods. A group of 17 patients received a 7-day infusion of etoposide (schedule A) every 21 days at doses from 30 to 75 mg/m2 per day, and a second group of 37 patients a 21-day infusion (schedule B) every 28 days at doses from 18 to 40 mg/m2 per day. Patients had a median Karnofsky performance status (PS) of 80%, and 34 patients had no prior chemotherapy. Etoposide
concentrations at steady state (Css) and other pharmacokinetic parameters (plasma clearance, CLp; area under the curve, AUC)
were determined during the first treatment cycle. Correlation coefficients were calculated to measure the relationship between
variables. Results. Myelosuppression was the major toxicity, and was associated with three deaths. The maximum tolerated dose due to neutropenia
was 75 mg/m2 per day for schedule A and 40 mg/m2 per day for schedule B. There was significant interpatient pharmacokinetic variability in both infusional schedules. Even
though etoposide dose levels did not significantly correlate with plasma levels, the Css was ≥1 μg/ml in the majority of the
patients. A significant correlation between AUC and neutrophil absolute decrease was noted only in schedule B (r=0.56, P=0.003). There were several marginal relationships in schedule B: PS versus Css (r=0.31, P=0.058), PS versus AUC (r=−0.38; P= 0.058) and age versus CLp (r=−0.31, P=0.057). Conclusion. Overall, significant correlations were found for several hematologic variables and etoposide dose levels, but not with the
Css values. One major problem with the application of pharmacodynamic models to predict hematologic toxicity in clinical practice
is the presence of significant interpatient variability.
Received: 3 April 1995/Accepted: 6 December 1995 相似文献
5.
Westermann AM Dubbelman R Baars JP Moolenaar WH Beijnen JH Rodenhuis S 《Cancer chemotherapy and pharmacology》2000,46(1):57-62
Purpose: Bioactive lipids have been causally linked to intraabdominal malignancies such as ovarian cancer. In advanced tumors confined
to the peritoneal cavity, inhibition of lipid growth factors present in ascites might induce tumor remissions. The systemic
toxicity of the growth factor inhibitor suramin has so far hampered its use in standard oncologic practice, but this could
be alleviated by intraperitoneal administration. In this study the feasibility, toxicity and pharmacokinetics of intraperitoneal
suramin administration are described. Methods: Patients with histologically verified cancer confined to the abdominal cavity, for which no effective therapy was available,
were treated with intraperitoneal suramin through a Tenckhoff catheter. Patients with ascites were treated with low-volume
continuous i.p. infusions of 500 mg/24 h, and patients without ascites were treated with intermittent large-volume i.p. infusions
of 1000 mg three times a week. Regular pharmacokinetic sampling of plasma and ascites fluid was carried out. Patients were
treated for 6 weeks or until development of progressive disease or until plasma suramin levels exceeded 250 mg/l. Results: Nine patients were treated in ten periods, three with intermittent i.p. suramin, and seven with continuous i.p. suramin,
for a median of 28.5 days (16–42 days), with a median suramin dose of 12 g (range 9–21 g ). Treatment was discontinued because
of high systemic suramin levels in three patients (all in the intermittent schedule), progressive disease (five patients)
or completion of planned treatment (one patient). Toxicity was mild, without any of the systemic side effects commonly associated
with suramin. Intraperitoneal suramin levels were consistently higher than plasma levels in all patients, but this effect
was most marked in the continuous infusion schedule. Conclusions: Intraperitoneal suramin infusion in patients with advanced peritoneal cancers is feasible and well-tolerated. Continuous
low volume i.p. infusion in patients with ascites confers the largest pharmacokinetic advantage.
Received: 5 July 1999 / Accepted: 15 February 2000 相似文献
6.
A Randomized Phase II Trial of Flutamide vs Chlormadinone Acetate in Previously Untreated Advanced Prostatic Cancer 总被引:1,自引:1,他引:0
Akaza Hideyuki; Usami Michiyuki; Kotake Toshihiko; Koiso Kenkichi; Aso Yoshio; The Japan Flutamide Study Group 《Japanese journal of clinical oncology》1993,23(3):178-185
We have conducted a double-blind comparative study of flutamideand chlormadinone acetate (CMA) on patients with stage C orD prostatic cancer and with no prior experience of hormone therapy.This is believed to be the first such trial entered in the medicalliterature, fifty-four patients were randomly selected to undergoflutamide (p.o.) monotherapy at a daily dose of 375 mg, whichwas determined as the optimal dose in Japan in our previousphase II study. Forty-nine others were randomly selected toundergo CMA (p.o.) monotherapy at a daily dose of 100 mg, whichis the most commonly used dosage in Japan for patients withprostatic cancer. Ultimately, 47 patients from the flutamidegroup and 40 patients from the CMA group were judged eligible,with efficacy being evaluated after 12 weeks of treatment. Similarobjective responses were seen in both groups: 48.9% (95% confidencelimits 34.163.9%) in the flutamide group, 45% (95% confidencelimits 29.361.5%) in the CMA group. The response at eachorgan site was also similar between the groups. Serum prostaticspecific antigen decreased by more than 50% of the abnormalpretreatment level in 87.5% of the flutamide group and in 85.7%of the CMA group. Serum luteinizing hormone, follicle-stimulatinghormone, testosterone and 5a-dihydrotestosterone decreased significantlyin the CMA group, but increased significantly in the flutamidegroup. The serum testosterone level after 12 weeks of treatmentwas 0.955±0.1 3 ng/ml in the CMA group and 6.64±0.38ng/ml in the flutamide group. The serum estradiol level alsoincreased significantly in patients in the flutamide group.The serum prolactin level decreased significantly in the flutamidegroup, but increased significantly in the CMA group. Eight patientson flutamide manifested gynecomastia. Diarrhea and hepatic toxicitywere observed in both groups, but only rarely, and were welltolerated. We have thus concluded that flutamide is as effectiveas CMA in maintaining libido and potency without decreasingtestosterone levels. 相似文献
7.
Federico Innocenti Romano Danesi Antonello Di Paolo Barbara Loru Claudio Favre Margherita Nardi Guido Bocci Denise Nardini Pierantonio Macchia Mario Del Tacca 《Cancer chemotherapy and pharmacology》1996,37(5):409-414
Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine (6-MP) and methotrexate (MTX) was investigated
in patients as well as in rats and in HL-60 human leukemic cells. Ten children affected by acute lymphoblastic leukemia (ALL)
in remission received daily doses of 6-MP given at 25 mg/m2 and i.v. infusion of high-dose MTX at 2 or 5 g/m2 once every other week. When 6-MP was given alone, the mean peak plasma concentration (Cmax) and area under the curve (AUC) of 6-MP were 72.5 ng/ml and 225.3 h ng ml-1. Concurrent treatment with MTX at 2 or 5 g/m2 resulted in a mean increase of 108% and 121% in the Cmax and of 69% and 93% in the AUC, respectively. In rats treated with an oral dose of 6-MP at 75 mg/m2, MTX given i.p. at 5 g/m2 produced mean increases of 110% and 230% in the Cmax and AUC of 6-MP, respectively. In HL-60 human leukemic cells incubated with 6-MP at 250 ng/ml, the cumulative intracellular
concentration of 6-thioguanine and 6-MP nucleotides was not significantly modified by treatment with 20 μg/ml of MTX. The
present findings indicate that high-dose MTX enhances the bioavailability of 6-MP as evidenced by the observed increases in
the plasma Cmax and AUC of 6-MP in humans and animals.
Received: 13 December 1994/Accepted: 12 July 1995 相似文献
8.
David S. Alberts Paul T. Fanta Kelli L. Running Laurence P. Adair Jr. Dava J. Garcia Rosa Liu-Stevens Sydney E. Salmon 《Cancer chemotherapy and pharmacology》1997,39(6):493-497
Purpose: To compare the in vitro cytotoxicity of nedaplatin, an investigational platinum analog, with that of the standard platinum
agents, cisplatin and carboplatin, against fresh human, epithelial ovarian cancers. Methods: The Hamburger-Salmon human tumor colony-forming assay (HTCA) was used to measure the chemosensitivity of 36 fresh tumor
samples obtained during initial exploratory laparotomy from patients with newly diagnosed stage III – IV epithelial ovarian
cancer who had received no prior chemotherapy or radiation therapy. Tumor samples were exposed to the platinum analogs for
1 h at concentrations of 10 and 100 μg/ml of nedaplatin and cisplatin and 100 and 1000 μg/ml of carboplatin. The resulting
survival data were used to estimate the IC50 (drug concentration associated with 50% inhibition of tumor colony forming units, TCFUs) of each of the platinum analogs
for each of the tumor samples, as well as the estimated survival following exposure to clinically achievable drug levels (i.e.
the ultrafiltrable platinum area under the plasma disappearance curve, AUC, achieved in cancer patients following administration
of standard or phase II doses). Results: At the lowest concentration tested (i.e. 10 μg/ml nedaplatin and cisplatin and 100 μg/ml carboplatin) the percentages of
tumor samples which were sensitive (as defined by 50% or less survival of TCFUs as compared with controls) were 42, 50, and
40% for nedaplatin, cisplatin and carboplatin, respectively. The median IC50 values were 28.5, 12 and 121 μg/ml for nedaplatin, cisplatin and carboplatin, respectively. The estimated percentage of tumors
sensitive to clinically achievable dose levels was 42% for nedaplatin and 36% for cisplatin and carboplatin. Nedaplatin and
carboplatin proved relatively crossresistant with cisplatin in vitro; of the 18 tumor samples which were resistant to cisplatin,
only 5 (28%) were sensitive to nedaplatin and 3 of 17 (18%) were sensitive to carboplatin. Conclusion: Nedaplatin was associated with cytotoxicity similar to cisplatin and carboplatin in this study. Although nedaplatin appears
to be crossresistant with cisplatin, its high rate of in vitro cytotoxicity, relative lack of neurotoxicity and nephrotoxicity,
and large in vivo bioavailability establish nedaplatin as a promising platinum analog for further clinical development as
a salvage and primary chemotherapeutic agent for patients with advanced ovarian cancer.
Received: 7 November 1995 / Accepted: 20 September 1996 相似文献
9.
Geoffrey R. Weiss John G. Kuhn Jinee Rizzo Lon S. Smith Gladys I. Rodriguez John R. Eckardt Howard A. Burris Suzanne Fields Karla VanDenBerg Daniel D. Von Hoff 《Cancer chemotherapy and pharmacology》1995,35(5):397-402
Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence
that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this
agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and
urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with
solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23
patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m2 per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected
before, during, and after drug infusion. The dose-limiting toxicity at 8.1 mg/m2 per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5
patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m2 per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (<1,000/μl) was observed at all dose levels
of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Nonhematological toxicities were
confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37°–40°C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state
(Cpss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m2 per day. Both the Cpss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between
the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination
of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m2 per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m2 per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study.
On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will
permit achievement of the concentrations consistent with antitumor activity observed in preclinical studies.
Received: 14 March 1994/Accepted: 22 July 1994 相似文献
10.
Rapoport B. L.; Falkson G.; Raats J. I.; de Wet M.; Lotz B. P.; Potgieter H. C. 《Annals of oncology》1993,4(7):567-573
BACKGROUND:: Hormone-resistant prostate cancer can respond to mitomycin Cor to suramin. This trial was undertaken to investigate thevalue of mitomycin C given with low dose suramin PATIENTS AND METHODS:: Thirty-two patients with hormonerefractory prostate cancer weregiven suramin 350 mg/m2 daily for 5 days, followed by 350 mg/m2weekly starting on day 14. Mitomycin C 12 mg/m2 was given every5 weeks starting on day 14. RESULTS:: Toxicity included maculo-papular skin rash in 8 patients, haematologicaltoxicity in 16 (anaemia 13, leucopenia 11 and thrombocytopenia9, bleeding 8), infection in 4 and fatigue in 11. Ten patientsdeveloped neurotoxicity, (temporary sensory peripheral neuropathyin 8, upper limb motor neuropathy in 1, and restless legs syndromein 1) and 9 developed proteinuria. Other toxicities were mildnausea and vomiting, oedema, transient elevation of liver enzymes,stomatitis, upper gastrointestinal symptoms, and alopecia. Duringinduction treatment the median trough suramin level was 140µg/ml (range 100273) and during maintenance treatmentthe median suramin level was 93 µg/ml. The median overalltrough level was 93 µg/ml. There were one complete and6 partial responses. Fifteen patients had disease stabilization.The median time to treatment failure was 103 days, and the mediansurvival 209 days. CONCLUSION:: The combination of suramin and mitomycin C has therapeutic activity,but causes significant toxicity in patients with hormone-resistantprostatic carcinoma. mitomycin C, prostate cancer, suramin 相似文献
11.
E. M. Newman Mary Carroll Steven A. Akman Warren Chow P. Coluzzi Victor Hamasaki Lucille A. Leong Kim A. Margolin Robert J. Morgan James W. Raschko Stephen Shibata George Somlo Merry Tetef Y. Yen Chul W. Ahn James H. Doroshow 《Cancer chemotherapy and pharmacology》1996,39(3):254-258
A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of
hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/m2 per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized
skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash,
but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations
of hydroxyurea were linearly correlated with the dose (R
2 = 0.71, n = 18, P<0.0001). The mean±SE concentrations were 93±16, 230±6 and 302±27 μM at 1, 2 and 3.2 g/m2 per day, respectively. The mean±SE renal and nonrenal clearances of hydroxyurea were 2.14±0.18 and 3.39±0.28 l/h per m2 (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with
a mean±SE half-life of 3.25±0.18 h (n = 17). The steady-state concentration of hydroxyurea was >200 μM in all nine patients treated at 2 g/m2 per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other
antineoplastic agents.
Received: 28 November 1995 / Accepted: 18 May 1996 相似文献
12.
Determination of vinca alkaloids in human plasma by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry 总被引:3,自引:0,他引:3
Jacqueline Ramírez Kenneth Ogan M. J. Ratain 《Cancer chemotherapy and pharmacology》1997,39(4):286-290
A sensitive assay was developed for the quantitation of vinblastine, desacetylvinblastine and vincristine using liquid chromatography-atmospheric
pressure chemical ionization mass spectrometry (LC-APCI-MS). Analyses were performed on an Ultrasphere C18 microbore column using ammonium acetate as mobile phase. The calibration curves were linear across the range of 0.51–4.00 ng/ml
(0.63–4.93 nM) for vinblastine, 0.74–3.93 ng/ml (0.96–5.11 nM) for desacetylvinblastine and 0.30–3.95 ng/ml (0.36–4.79 nM) for vincristine. Vinca alkaloid concentrations were measured with an accuracy and precision within 11%. This assay could
be implemented to determine the plasma concentrations for pharmacokinetic studies of vinblastine, desacetylvinblastine and
vincristine in conjunction with clinical trials.
Received: 15 December 1995 / Accepted: 16 June 1996 相似文献
13.
Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis 总被引:10,自引:0,他引:10
Tetef ML Margolin KA Doroshow JH Akman S Leong LA Morgan RJ Raschko JW Slatkin N Somlo G Longmate JA Carroll MI Newman EM 《Cancer chemotherapy and pharmacology》2000,46(1):19-26
Purpose: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients
with meningeal carcinomatosis. Methods: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma
were treated with MTX at loading doses of 200–1500 mg/m2, followed by a 23-h infusion of 800–6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared
in patients with and without central nervous system (CNS) disease. Results: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease,
who all had CSF MTX concentrations above the target cytotoxic concentration (1 μM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses.
The mean half-life of CSF MTX was 8.7 ± 3.4 h. The mean plasma clearance of MTX was not significantly different in patients
with CNS disease (84 ± 41 ml/min per m2) versus without CNS disease (59 ± 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF.
Conclusion: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (>1 μM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX.
Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.
Received: 4 May 1999 / Accepted: 14 February 2000 相似文献
14.
Flavone acetic acid increases the cytotoxicity of mitomycin C when combined with hyperthermia 总被引:4,自引:0,他引:4
H. Takeuchi Hideo Baba Yoshihiko Maehara Keizo Sugimachi Robert A Newman 《Cancer chemotherapy and pharmacology》1996,38(1):1-8
Flavone acetic acid (FAA, NSC 347512) is known to selectively reduce tumor blood flow. Taking advantage of this pharmacodynamic
effect, we have previously shown that FAA in combination with hyperthermia (HT) can produce a marked improvement in antitumor
response in mice. In the present study, we investigated whether FAA could increase the cytotoxicity of mitomycin C (MMC),
a bioreductive drug with selective cytotoxicity against hypoxic cells, under either normothermic or hyperthermic conditions.
In vitro, the cytotoxicity of MMC against B16 melanoma cells was not enhanced with exposure to FAA at concentrations less than 100 μg/ml,
even when combined with HT (43°C, 60 min). The cytotoxicity of MMC (1 μg/ml) at pH 6.5, however, was enhanced by exposure
of cells to hypoxia in combination with HT. In vivo, the tumor growth time, calculated as the time required to double the initial tumor volume, was 5.2, 6.8, 8.5, and 15.0 days
with FAA (150 mg/kg) alone, MMC (4 mg/kg) alone, FAA+MMC, or FAA+MMC+HT (43°C, 15 min) treatment groups, respectively. Antitumor
response obtained in animals treated with FAA plus MMC with HT was clearly better than that obtained in any of the other groups.
Scheduling of FAA, MMC, and HT was found to be important in producing optimal antitumor response. Administration of MMC (4 mg/kg)
prior to FAA (150 mg/kg) and subsequent HT treatment was superior to administration of FAA before MMC. In an attempt to explain
these findings, the influence of FAA on blood flow in skeletal muscle and in tumor was examined using a laser blood flowmeter.
FAA administration to mice produced a 75% reduction in blood flow to the tumor for up to 2 h but had no detectable effect
on normal skeletal blood flow. Our current explanation of the increased antitumor response achieved with the combination of
MMC, FAA, and HT is as follows. The FAA-mediated decrease in blood flow to the tumor, when combined with HT, may produce sufficiently
hypoxic conditions to significantly increase the antitumor efficacy of the bioreductive drug, MMC. We believe that clinical
testing of this combined drug treatment with hyperthermia is warranted.
Received: 1 February 1995/Accepted: 6 July 1995 相似文献
15.
Lorraine K. Webster Nicholas A. Crinis Carmel G. Morton Michael J. Millward 《Cancer chemotherapy and pharmacology》1996,37(5):499-501
Paclitaxel is formulated in 50% Cremophor EL and 50% ethanol such that patients receiving paclitaxel also receive a significant
amount of each of these solvents. The aim of this study was to measure the plasma alcohol levels in patients treated with
paclitaxel. A total of 12 patients who were enrolled in phase II trials of non-small-cell lung cancer, breast cancer or ovarian
cancer received 175 mg/m2 paclitaxel given as a 3-h infusion. Blood samples were obtained prior to and immediately following the infusion, and plasma
ethanol concentrations were measured enzymatically. The dose of ethanol delivered with the paclitaxel ranged from 20.0 to
28.9 ml. No alcohol was detected in pre-dose plasma, but 8 of 12 patients had detectable levels in post-infusion plasma, with
0.033 g/dl being the highest concentration. The elimination rate of alcohol approximates the infusion rate when paclitaxel
is given over 3 h, resulting in low or undetectable levels in most patients. However, in patients receiving an equivalent
dose of paclitaxel given as a 1-h infusion, the plasma alcohol levels will likely be high enough for significant pharmacological
effects to occur.
Received 14 May 1995/Accepted: 4 August 1995 相似文献
16.
G. S. Harman George A. Omura Kevin Ryan John D. Hainsworth Michael B. Cramer William F. Hahne 《Cancer chemotherapy and pharmacology》1996,38(4):323-328
Purpose: Intravenous dolasetron has been shown to be an effective antiemetic agent in patients receiving high-dose cisplatin-containing
chemotherapy. Previous studies have suggested that 1.8 mg/kg is an optimal dose for achieving control of emesis and nausea.
The objective of this study was to compare the efficacy and safety of a single intravenous (IV) dose of dolasetron with an
equal divided multiple dose. Methods: In this randomized, double-blind, parallel-group, multicenter study, the efficacy and safety of a single 1.8-mg/kg dose of
dolasetron given 30 min prior to high-dose cisplatin (≥80 mg/m2) chemotherapy was compared with the same total amount of dolasetron administered in three separate doses (0.6 mg/kg each)
over a 12-h interval commencing 30 min prior to beginning chemotherapy and ending 11.5 h later. Antiemetic efficacy, safety,
and tolerability were compared in 55 patients with various malignancies during the 24 h following the initiation of chemotherapy.
The number of emetic episodes was the primary efficacy parameter. Results: A single IV dose of dolasetron was generally more effective than a multiple-dose regimen in all measures of efficacy. There
was a larger proportion of complete responders in the single-dose group compared with the multiple-dose group (48% vs 23%),
although this difference did not reach statistical significance. Compared with the multiple-dose group, patients who received
a single dose of dolasetron had a significantly (P=0.034) longer median time to the first emetic episode (10.1 h vs >24 h, respectively). Overall, 53% of patients had either
a complete response or a major response to dolasetron, and only 40% of the total patient population received escape antiemetic
medication in the 24 h after cisplatin administration. Except for headache, adverse events were similar with both regimens
and were generally of mild or moderate intensity; no serious adverse events occurred. Neither dolasetron treatment regimen
was associated with any clinically important events, trends in laboratory variables, or differences in safety profile. Conclusions: single-dose dolasetron was well tolerated and effectively controlled emesis and nausea in patients who received highly emetogenic,
high-dose cisplatin chemotherapy. The greater antiemetic efficacy of a single prophylactic dose of dolasetron offers both
convenience and potential cost savings, compared with a multiple-dose schedule of administration.
Received: 31 March 1995/Accepted: 20 October 1995 相似文献
17.
Legnani FG Pradilla G Thai QA Fiorindi A Recinos PF Tyler BM Gaini SM DiMeco F Brem H Olivi A 《Journal of neuro-oncology》2006,77(3):225-232
Summary Lactacystin, a proteasome-inhibitor, has been shown to induce apoptosis of experimental gliomas in vitro. However, its systemic toxicity prevents further clinical use. To circumvent this problem, lactacystin can be delivered intratumorally.
We tested the efficacy of lactacystin incorporated into controlled-release polymers for treating experimental gliomas. 9L-gliosarcoma
and F98-glioma cell lines were treated with lactacystin (10–100 μg/ml) for 72 h in vitro. Cell-viability was measured with MTT-assays. Toxicity of lactacystin/polycarboxyphenoxypropane-sebacic-acid (pCPP : SA)
polymers was tested in vivo using Fischer-344 rats intracranially implanted with lactacystin polymers loaded from 0.1 to 2% lactacystin by weight. The
efficacy of 1, 1.3, 1.5 and 1.7% lactacystin/pCPP : SA polymers was determined in Fischer-344 rats intracranially challenged
with 9L and treated either simultaneously or 5 days after tumor implantation. Lactacystin was cytotoxic in 9L cells, causing
a 16 ± 8% growth inhibition at 10-μg/ml that increased to 78 ± 4% at 100-μg/ml. Similarly, lactacystin inhibited growth of
F98 by 18 ± 8% at 10-μg/ml and 74 ± 2% at 100-μg/ml in vitro. Polymers released lactacystin for 21 days and intracranial implantation in rats neither generate local nor systemic toxicity
at doses lower than 2%. Treatment with lactacystin/pCPP : SA polymers with loading concentrations of 1.0, 1.3, and 1.5% prolonged
survival of animals intracranially challenged with 9L when polymers where inserted in the day of tumor implantation. In conclusion,
lactacystin exhibits potent cytotoxic-activity against 9L and F98 in vitro, it can be efficiently incorporated and delivered using controlled-release polymers, and at the proposed concentrations lactacystin
polymers are safe for CNS delivery and prolong survival in the 9L model.
These authors equally contributed in all aspects of this study. 相似文献
18.
Guido Bocci Romano Danesi Umberto Benelli Federico Innocenti Antonello Di Paolo Stefano Fogli Mario Del Tacca 《Cancer chemotherapy and pharmacology》1999,43(3):205-212
The aim of the present study was to test the ability of the chemotherapeutic agent suramin to inhibit angiogenesis in experimental
models in vitro and in vivo. In the culture of rat aortic rings on fibronectin, suramin dose-dependently inhibited vascular
cell growth, achieving the maximal effect (mean − 88% versus controls, P < 0.05) at 400 μg/ml. Image analysis showed that suramin could inhibit microvessel sprouting in fibrin from rat aortic rings
as evaluated by the ratio between the cellular area and the mean gray value of the sample (sprouting index); suramin at 50 μg/ml
significantly reduced the sprouting index from the control value of 0.35 ± 0.04 to 0.14 ± 0.02 mm2/gray level (P < 0.05). Likewise, the area occupied by cells was 19.2 ± 1.8 mm2 as compared with 41.8 ± 4.2 mm2 in controls (P < 0.05). In the rat model of neovascularization induced in the cornea by chemical injury, suramin at 1.6 mg/eye per day reduced
the length of blood vessels (0.7 ± 0.1 mm as compared with 1.5 ± 0.1 mm in controls, P < 0.05). In the same model the ratio between the area of blood vessels and the total area of the cornea (area fraction score)
was decreased by suramin from 0.19 ± 0.02 in controls to 0.03 ± 0.003 (P < 0.05). Suramin given i.p. at 30 mg/kg per day markedly inhibited the neovascularization induced in the rat mesentery by
compound 48/80 or conditioned medium from cells secreting the angiogenic protein fibroblast growth factor-3 (FGF-3). The area
fraction score in control rats treated with compound 48/80 was 0.31 ± 0.03, and this was reduced to 0.07 ± 0.01 by suramin
(P < 0.05). After i.p. administration of FGF-3 the area fraction score was reduced by suramin from 0.29 ± 0.03 to 0.05 ± 0.01
(P < 0.05). These results provide evidence that suramin exerts inhibitory effects on angiogenesis in both in vitro and in vivo
models.
Received: 9 January 1998 / Accepted: 29 June 1998 相似文献
19.
Etienne Chatelut Christine Chevreau Valérie Brunner Mathilde Martinez Georges Houin Roland Bugat Pierre Canal 《Cancer chemotherapy and pharmacology》1995,35(5):391-396
Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study
of carboplatin in combination with methotrexate (30 mg/m2) and vinblastine (4 mg/m2) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable
carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage
of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method
allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired
renal function. The recommended AUC for phase II study is 4 mg ml-1 min.
Received: 9 May 1994/Accepted: 16 August 1994 相似文献
20.
Stereoselective pharmacokinetics of ifosfamide and its 2- and 3-N-dechloroethylated metabolites in female cancer patients 总被引:1,自引:0,他引:1
Camille P. Granvil Julie Ducharme Brian Leyland-Jones Marc Trudeau Irving W. Wainer 《Cancer chemotherapy and pharmacology》1996,37(5):451-456
The pharmacokinetics of the R and S enantiomers of ifosfamide (IFF) and of its 2- and 3-N-dechloroethylated metabolites (2-DCE-IFF and 3-DCE-IFF) were investigated in 14 cancer patients treated with a 3-h infusion
of (R,S)-IFF (3 g/m2) with mesna uroprotection. An enantioselective gas chromatographic-mass spectrometric (GC-MS) assay was used to determine
the concentrations in plasma and urine. The AUCs of (R)-IFF were significantly larger than those of (S)-IFF (2480±200 vs 1960±150 μM . h). The terminal half-lives (7.57±0.99 h) and mean residence times (11.17±1.10 h) of (R)-IFF were significantly longer than those of (S)-IFF, 6.03±0.82 h and 9.37±0.88 h, respectively. The mean volume of distribution at steady state of (R)-IFF (25.68±0.80 l/m2) was slightly smaller than that of (S)-IFF (27.35±0.89 l/m2). While the renal clearances of (R)-IFF and (S)-IFF were similar, the nonrenal clearance was significantly lower for (R)-IFF (30.20±2.70 vs 41.40±3.55 ml/m2 per min) as was total clearance (41.52±2.90 vs 52.37±3.75 ml/m2 per min). The AUC values for all of the DCE metabolites from (S)-IFF were significantly greater than those from (R)-IFF with 47% of the measured AUC accounted for by DCE from (S)-IFF compared to only 20% for (R)-IFF. Therefore, the enantioselective difference in IFF elimination can be partially explained by differences in N-dechloroethylation.
Received: 13 December 1994/Accepted: 14 May 1995 相似文献