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1.
J Dent Res ; 95(2): 173-9, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26553883

ABSTRACT

The purpose of this study was to assess the relationship between vitamin D status and dental caries in Canadian school-aged children participating in the Canadian Health Measures Survey (CHMS). The CHMS was a national cross-sectional study involving physical assessments, laboratory analysis, and interviews. Analysis was restricted to data for 1,017 children 6 to 11 y of age. Outcome variables included the presence of caries and overall total caries score (dmft/DMFT index). Levels of 25-hydroxyvitamin D (25(OH)D) were measured from serum samples obtained from participants. Bivariate analysis, logistic regression for the presence of caries, and multiple linear regression for total caries scores were used. Significance was set at P ≤ 0.05. Overall, 56.4% of children experienced caries, and the mean dmft/DMFT score was 2.47 (95% CI 2.09 to 2.84). The unadjusted odds of children with 25(OH)D levels ≥75 nmol/L having experienced caries was 0.57 (95% CI 0.39 to 0.82), while the odds for caries at the ≥50 nmol/L level was 0.56 (95% CI 0.39 to 0.89). After controlling for other covariates, backward logistic regression revealed that the presence of caries was significantly associated with 25(OH) levels <75 nmol/L and <50 nmol/L, lower household education, not brushing twice daily, and yearly visits to the dentist. Similarly, multiple linear regression revealed that total dmft/DMFT caries scores were also associated with 25(OH)D concentrations <75 nmol/L, not brushing twice daily, lower household education, and yearly visits to the dentist. Data from a cross-sectional, nationally representative sample of Canadian children suggest that there is an association between caries and lower serum vitamin D. Improving children's vitamin D status may be an additional preventive consideration to lower the risk for caries.


Subject(s)
Dental Caries/epidemiology , Vitamin D/analogs & derivatives , Vitamins/blood , Canada/epidemiology , Child , Cross-Sectional Studies , DMF Index , Dental Care/statistics & numerical data , Educational Status , Family Characteristics , Female , Humans , Income/statistics & numerical data , Male , Tooth, Deciduous/pathology , Toothbrushing/statistics & numerical data , Vitamin D/blood
2.
Oncology ; 73(5-6): 305-10, 2007.
Article in English | MEDLINE | ID: mdl-18493157

ABSTRACT

PURPOSE: It was the aim of this study to assess the risk of lung cancer in postmenopausal women who received hormone replacement therapy (HRT). EXPERIMENTAL DESIGN: This case-control study involves women who received medical services at Roswell Park Cancer Institute (RPCI) in Buffalo, New York, between 1982 and 1998, and who agreed to complete an epidemiological questionnaire. Participants with missing smoking data were excluded. The case group consisted of 595 women with primary lung cancer. Controls included 1,195 women, randomly selected from a pool of 5,845 eligible individuals, who received medical services at RPCI for non-neoplastic conditions; they had come to RPCI with a suspicion of neoplastic disease, but were diagnosed with neither benign nor malignant conditions. Controls were frequency matched 2:1 to cases on 5-year age intervals and exposure to smoking (ever/never). Cases and controls were comparable for age (means 61.3 and 61.0 years) and ever smoking (90%). RESULTS: There were more former smokers among the cases (67 vs. 59% in controls); cases were less likely to be high school educated, were thinner, and were less likely to report HRT use compared with controls. Overall, hormone use was associated with a significant reduction in risk of lung cancer (adjusted odds ratio = 0.67; 95% confidence interval 0.53-0.85). Stratified analyses showed significant reductions in lung cancer risk in former smokers and women with normal to low body mass index. CONCLUSION: This study supports the hypotheses that there is a protective effect of HRT use on lung cancer risk in women.


Subject(s)
Carcinoma, Non-Small-Cell Lung/chemically induced , Estrogen Replacement Therapy/adverse effects , Lung Neoplasms/chemically induced , Adult , Aged , Aged, 80 and over , Body Weight , Case-Control Studies , Female , Humans , Middle Aged , Obesity/epidemiology , Retrospective Studies , Risk Factors , Smoking/adverse effects , Surveys and Questionnaires
3.
Article in English | MEDLINE | ID: mdl-12113985

ABSTRACT

A new liquid chromatographic method is described for the determination of the anti-tumour agent bexarotene in human plasma over the range 0.500-1500 ng/ml, using 1 ml of sample. Sample preparation consists of liberating the analyte from plasma lipids by adding acetonitrile, followed by acidification of the plasma and liquid extraction using a mixture of isoamyl alcohol and pentane or hexane. Separation and quantitation are performed by reversed-phase column liquid chromatography with fluorescence detection. Parameters affecting the performance of these steps are discussed. Validation results on linearity, selectivity, accuracy, precision, recovery and stability are shown, as well as the application of the method to samples from clinical trials.


Subject(s)
Chromatography, Liquid/methods , Tetrahydronaphthalenes/blood , Bexarotene , Calibration , Humans , Reference Standards , Reproducibility of Results , Sensitivity and Specificity , Spectrometry, Fluorescence , Tetrahydronaphthalenes/pharmacokinetics
4.
BMC Cancer ; 1: 6, 2001.
Article in English | MEDLINE | ID: mdl-11472637

ABSTRACT

BACKGROUND: Because cells progressing to cancer must proliferate, marker proteins specific to proliferating cells may permit detection of premalignant lesions. Here we compared the sensitivities of a classic proliferation marker, Ki-67, with a new proliferation marker, MCM2, in 41 bronchial biopsy specimens representing normal mucosa, metaplasia, dysplasia, and carcinoma in situ. METHODS: Parallel sections were stained with antibodies against MCM2 and Ki-67, and the frequencies of staining were independently measured by two investigators. Differences were evaluated statistically using the two-sided correlated samples t-test and Wilcoxon rank sum test. RESULTS: For each of the 41 specimens, the average frequency of staining by anti-MCM2 (39%) was significantly (p < 0.001) greater than by anti-Ki-67 (16%). In metaplastic lesions anti-MCM2 frequently detected cells near the epithelial surface, while anti-Ki-67 did not. CONCLUSIONS: We conclude that MCM2 is detectable in 2-3 times more proliferating premalignant lung cells than is Ki-67. The promise of MCM2 as a sensitive marker for premalignant lung cells is enhanced by the fact that it is present in cells at the surface of metaplastic lung lesions, which are more likely to be exfoliated into sputum. Future studies will determine if use of anti-MCM2 makes possible sufficiently early detection to significantly enhance lung cancer survival rates.


Subject(s)
Biomarkers, Tumor , Lung Neoplasms/diagnosis , Nuclear Proteins , Precancerous Conditions/diagnosis , Bronchi/chemistry , Bronchi/pathology , Cohort Studies , Disease-Free Survival , Epithelial Cells/chemistry , Epithelial Cells/pathology , Humans , Immunohistochemistry , Ki-67 Antigen/biosynthesis , Lung Neoplasms/chemistry , Lung Neoplasms/pathology , Minichromosome Maintenance Complex Component 2 , Nuclear Proteins/biosynthesis , Precancerous Conditions/chemistry , Precancerous Conditions/pathology
5.
Arch Dermatol ; 136(12): 1461-9, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11115156

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of topical alitretinoin gel (9-cis-retinoic acid [LGD1057], Panretin gel; Ligand Pharmaceuticals, Inc, San Diego, Calif) in cutaneous Kaposi sarcoma (KS). DESIGN: Open-label, within-patient, controlled, dose-escalating phase 1 and 2 clinical trials. In all patients, 1 or more cutaneous KS lesions were treated with alitretinoin gel, and at least 2 other lesions served as untreated controls for up to 16 weeks. Alitretinoin (0.05% or 0.1% gel) was applied twice daily for the first 2 weeks and up to 4 times daily thereafter, if tolerated. SETTING: Nine academic clinical centers. PATIENTS: One hundred fifteen patients with biopsy-proven acquired immunodeficiency syndrome (AIDS)-related KS. MAIN OUTCOME MEASURES: AIDS Clinical Trials Group response criteria. RESULTS: Statistically significant clinical responses were observed in 31 (27%) of 115 patients for the group of treated index lesions compared with 13 (11%) for the group of untreated control lesions (P<.001). Responses occurred with low CD4(+) lymphocyte counts (<200 cells/microL) and in some patients with refractory response to previous systemic anti-KS therapy. The incidence of disease progression was significantly lower for treated index lesions compared with untreated control lesions (39/115 [34%] vs 53/115 [46%]; P =.02). Alitretinoin gel generally was well tolerated, with 90% of treatment-related adverse events confined to the application site and only mild or moderate in severity. CONCLUSIONS: Alitretinoin gel has significant antitumor activity as a topical treatment for AIDS-related KS lesions, substantially reduces the incidence of disease progression in treated lesions, and is generally well tolerated.


Subject(s)
AIDS-Related Opportunistic Infections/drug therapy , Antineoplastic Agents/therapeutic use , Sarcoma, Kaposi/drug therapy , Skin Neoplasms/drug therapy , Tretinoin/therapeutic use , AIDS-Related Opportunistic Infections/pathology , Administration, Cutaneous , Adult , Alitretinoin , Antineoplastic Agents/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Gels , Humans , Male , Middle Aged , Sarcoma, Kaposi/pathology , Skin Neoplasms/pathology , Treatment Outcome , Tretinoin/administration & dosage , United States
6.
Ann Oncol ; 11(11): 1387-9, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11142476

ABSTRACT

Although advanced renal-cell carcinoma (RCC) responds poorly to standard therapies, phase I-II trials have shown activity for combinations of interferon-alpha2b (IFN) with a retinoid. Alitretinoin (9-cis RA) is an endogenous retinoid with high binding affinity for both RAR and RXR receptor families. This phase I-II study enrolled 38 patients with RCC in a dose-escalation study of tolerability, pharmacokinetics (PK), and efficacy of twice daily oral 9-cis RA with subcutaneous IFN. In contrast to studies with similar doses of daily 9-cis RA, PK studies found a consistent reduction in 9-cis RA concentrations of about 50% after multiple b.i.d. doses of 30 or 50 mg/m2, independent of cotreatment with IFN. In the phase I portion, toxicities included systemic symptoms typical of IFN and biochemical abnormalities previously associated with retinoids. Two patients experienced dose-limiting toxicity at 50 mg/m2 b.i.d. of 9-cis RA, thus the recommended phase II dose was 30 mg/m2 b.i.d. One of twenty-six evaluable patients achieved a durable objective partial remission, and repeated dosing with this regimen was poorly tolerated. This combination of retinoid and interferon is not recommended for further study in RCC.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Immunologic Factors/therapeutic use , Interferon-alpha/therapeutic use , Kidney Neoplasms/drug therapy , Tretinoin/therapeutic use , Adult , Aged , Alitretinoin , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Chemical and Drug Induced Liver Injury/etiology , Combined Modality Therapy , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Synergism , Fatigue/chemically induced , Female , Fever/chemically induced , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Immunologic Factors/pharmacokinetics , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Interferon-alpha/pharmacokinetics , Male , Middle Aged , Nephrectomy , Pain/chemically induced , Recombinant Proteins , Remission Induction , Treatment Failure , Tretinoin/administration & dosage , Tretinoin/adverse effects , Tretinoin/pharmacokinetics
7.
Clin Cancer Res ; 5(7): 1658-64, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10430065

ABSTRACT

LGD1069 [Targretin; 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid] is a novel synthetic retinoid X receptor-selective retinoid that has been recently identified. The goals of this study were to determine the safety, toxicity, pharmacokinetics (PKs), and metabolic profile of LGD1069 in advanced cancer patients. Sixty patients received oral LGD1069 at doses ranging from 5-1000 mg/m2/day with PK sampling performed on days 1 and 15. No dose-limiting toxicities (DLTs) were observed up to the 500 mg/m2/day dose level. DLT observed at and above 650 mg/m2/day included skin desquamation, hyperbilirubinemia, transaminase elevation, leukopenia, and diarrhea. Asymptomatic, dose-related alterations in lipid and thyroid metabolism were also observed. DLTs frequently observed with retinoic acid receptor-selective retinoids and pan agonists, including headache, mucocutaneous toxicity, and hypercalcemia, were not dose-limiting with LGD1069. Day 1 LGD1069 Cmax and area under the curve values increased dose-proportionately up to 800 mg/m2/day. Repeat-dose (day 15) area under the curve values varied between 25 and 105% of day 1 values. Although no objective tumor responses were observed, tumor progression may have been substantially arrested or delayed in non-small cell lung cancer (5 of 16) and in head and neck cancer (1 of 5), as well as other tumor types. At the higher dose levels, the molar concentration of LGD1069 was up to 10-fold higher than observed with other retinoids, yet toxicity was minimal. LGD1069 is an retinoid X receptor-selective retinoid agonist with a more favorable PK and toxicity profile than previously studied retinoids and merits further investigation as a chemopreventive and anticancer agent. On the basis of this Phase I trial, the recommended Phase II dose is 500 mg/m2/day.


Subject(s)
Anticarcinogenic Agents/therapeutic use , Neoplasms/drug therapy , Tetrahydronaphthalenes/therapeutic use , Adult , Aged , Aged, 80 and over , Anticarcinogenic Agents/adverse effects , Anticarcinogenic Agents/pharmacokinetics , Bexarotene , Female , Headache/chemically induced , Humans , Leukopenia/chemically induced , Male , Middle Aged , Neoplasm Staging , Neoplasms/metabolism , Tetrahydronaphthalenes/adverse effects , Tetrahydronaphthalenes/pharmacokinetics , Treatment Outcome
8.
Cancer J Sci Am ; 5(3): 165-70, 1999.
Article in English | MEDLINE | ID: mdl-10367173

ABSTRACT

PURPOSE: 9-cis retinoic acid (ALRT 1057; 9cRA) is a promising new retinoid that binds to all known retinoic acid receptors (RAR and RXR), potentially providing it with a broader spectrum of biologic activity than either 13-cis retinoic acid or all-trans retinoic acid. It has been shown to be at least as active as all-trans retinoic acid as a differentiation-inducing and antiproliferative agent in both in vivo and in vitro tumor model systems. METHODS: The New York Gynecologic Oncology Group undertook a prospective, multi-institutional phase II clinical and pharmacokinetic trial of 9cRA in patients with advanced or recurrent squamous cell or adenosquamous cell carcinoma of the uterine cervix. Patients received daily oral doses of 140 mg/m2 of 9cRA. 9cRA and its metabolites were determined by reversed-phase HPLC in plasma samples drawn at 0.5 to 8 hours. RESULTS: Sixteen patients with advanced or recurrent carcinoma of the cervix were enrolled. Therapy was well tolerated with no unexpected toxicities. There were no complete or partial responses observed, indicating that a response rate of 20% or greater to this agent could be ruled out with 95% confidence. Pharmacokinetic parameters for 9cRA on day 1 were in agreement with previous studies. The area under the plasma versus time curves for 9cRA declined by 69% between days 1 and 8 with daily 9cRA dosing and remained at this low level in those patients evaluated on day 28. 4-oxo-9-cis retinoic acid (4-oxo-9cRA) was identified as a major plasma metabolite of 9cRA. Plasma levels of 4-oxo-9-cRA were initially 71% of those of 9cRA, but in contrast to 9cRA, there was no decline in plasma levels on days 8 and 28. The ratio of the area under the curve for the 4-oxo metabolite relative to that of the parent compound increased from less than 1 on day 1 to approximately 2.4 on days 8 and 28. Thus, despite early induction of its own metabolism, levels of total retinoid metabolites persisted at pharmacologic levels at day 28. CONCLUSIONS: 9cRA with this dose and schedule was inactive in women with advanced carcinoma of the cervix. Despite a decline in plasma levels of 9cRA over time, levels of the 4-oxo metabolite tended to persist. While the 4-oxo metabolite is less potent than the parent compound, these data nevertheless suggest that the lack of clinical activity in this patient population may not be attributable exclusively to suboptimal pharmacokinetic parameters.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Adenosquamous/drug therapy , Carcinoma, Squamous Cell/drug therapy , Tretinoin/therapeutic use , Uterine Cervical Neoplasms/drug therapy , Adult , Aged , Alitretinoin , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Carcinoma, Adenosquamous/metabolism , Carcinoma, Squamous Cell/metabolism , Female , Humans , Middle Aged , Prospective Studies , Treatment Outcome , Tretinoin/adverse effects , Tretinoin/pharmacokinetics , Uterine Cervical Neoplasms/metabolism
9.
Clin Cancer Res ; 4(6): 1437-42, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9626460

ABSTRACT

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/toxicity , Neoplasms/drug therapy , Tretinoin/pharmacokinetics , Tretinoin/toxicity , Administration, Oral , Adult , Aged , Aged, 80 and over , Alitretinoin , Antineoplastic Agents/administration & dosage , Capsules , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Tretinoin/administration & dosage
10.
J Pharm Biomed Anal ; 16(6): 1013-9, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9547704

ABSTRACT

A HPLC method was developed and validated for the quantitation of 9-cis-retinoic acid (ALRT1057) and its major metabolite, 4-oxo-9-cis-retinoic acid (LG100182) in human plasma. Samples were buffered and extracted with methyl-tert-butyl-ether. The analytes and an I.S. were separated on a C18 HPLC column using a shallow gradient of 70-89% organic solvent. The analytes were quantitated by UV detection at 348 nm. Selectivity against endogenous compounds and potential metabolites (retinol, all trans-, 13-cis-, and 4-hydroxy-9-cis-retinoic acid) was demonstrated. The run time was 29 min. The standard curve was linear from 2.5 to 450 ng ml-1. Interassay precision for both analytes in quality control samples was less than 5.0% RSD. Accuracy was within 11.0% RE for both compounds. Analyte stability during sample storage, extraction processing, and chromatography was established. Method ruggedness was tested by two analysts and on two HPLC systems. This method has been applied to the quantitation of clinical samples.


Subject(s)
Tretinoin/analogs & derivatives , Tretinoin/blood , Alitretinoin , Calibration , Chromatography, High Pressure Liquid , Humans , Indicators and Reagents , Quality Control , Reference Standards , Reproducibility of Results , Solutions
11.
J Nat Prod ; 61(2): 251-2, 1998 Feb 27.
Article in English | MEDLINE | ID: mdl-9548854

ABSTRACT

A novel lactone, gloeolactone (1), has been isolated from the blue-green alga, Gloeotrichia sp. The structure of this compound has been elucidated from a detailed analysis of the NMR spectra. This compound was shown to be toxic to brine shrimp.

12.
Cancer Chemother Pharmacol ; 41(2): 167-70, 1998.
Article in English | MEDLINE | ID: mdl-9443631

ABSTRACT

PURPOSE: To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters of a 10-day infusion of the nonclassical antifolate Thymitaq. METHODS: The drug was given by 10-day infusion via a portable pump. The starting dose was 286 mg/m2 per day with escalation to 572 and 716 mg/m2 per day. Thymitaq in plasma was assayed by a validated isocratic reverse-phase HPLC assay with detection at 273 nm. RESULTS: The dose of 716 mg/m2 per day x 10 was considered too high as none of three patients completed a 10-day infusion and two of three developed grade IV myelotoxicity. At 572 mg/m2 per day three of four patients completed a 10-day infusion. Dose-limiting myelosuppression was seen in one of four but owing to a high incidence of thrombotic phenomena, no further patients were added. CONCLUSION: Continuous 10-day infusions of Thymitaq should be limited to low doses until further studies can be done.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Neoplasms/drug therapy , Quinazolines/administration & dosage , Adult , Aged , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/blood , Antimetabolites, Antineoplastic/pharmacokinetics , Area Under Curve , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Humans , Infusions, Intravenous , Middle Aged , Quinazolines/adverse effects , Quinazolines/blood , Quinazolines/pharmacokinetics
13.
Semin Oncol ; 24(4 Suppl 12): S12-138-S12-143, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9331139

ABSTRACT

The combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion followed by carboplatin infused over 30 minutes has been evaluated in a series of phase I studies and is currently being explored in a phase II study in patients with limited- and extensive-stage small cell lung cancer. Pharmacokinetic measurements were performed at all dose levels in the phase I studies, in which the use of granulocyte colony-stimulating factor in previously treated patients enabled more than twice the dose of paclitaxel to be given with low to moderate doses of carboplatin (dosed to a target area under the concentration-time curve of 4.0 mg x min x mL[-1]). Treatment-naive patients tolerated high paclitaxel doses (270 mg/m2) with carboplatin (dosed to a target area under the curve of 4.5 mg x min x mL[-1]) without granulocyte colony-stimulating factor support. Twenty-three patients (including previously treated and untreated) with non-small cell lung cancer were entered at a variety of paclitaxel doses in the phase I studies. At 100 to 205 mg/m2 paclitaxel, none of nine treated patients responded; at 230 to 290 mg/m2, four (29%) of 14 responded. In the phase II study of paclitaxel 250 mg/m2 in previously untreated patients with small cell lung cancer, two of five evaluable patients with extensive-stage disease have shown a partial response. In a preliminary analysis of the pharmacodynamics of paclitaxel in relation to neurotoxicity (dose limiting in two of three phase I studies), neurotoxicity correlated with the total dose of paclitaxel, the area under the curve, and the peak paclitaxel concentration, but not with the length of time plasma paclitaxel levels remained above 0.05 micromol/L. These correlations were not strong, however, and analysis of these data is ongoing.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Small Cell/drug therapy , Lung Neoplasms/drug therapy , Paclitaxel/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carboplatin/administration & dosage , Carboplatin/pharmacokinetics , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Humans , Paclitaxel/pharmacokinetics
14.
Am J Med Sci ; 314(2): 124-5, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9258216

ABSTRACT

Malignancies can cause mediastinal and hilar lymphadenopathy that is easily mistaken for sarcoidosis. We report a patient with breast cancer who initially had respiratory symptoms and thoracic lymphadenopathy. Despite the rarity of breast cancer manifesting in this way, the importance of obtaining histologic confirmation of suspected sarcoidosis is stressed.


Subject(s)
Adenocarcinoma/diagnosis , Breast Neoplasms/pathology , Adenocarcinoma/secondary , Diagnosis, Differential , Female , Humans , Lymphatic Metastasis/diagnosis , Middle Aged , Sarcoidosis, Pulmonary/diagnosis
15.
J Clin Oncol ; 15(2): 790-5, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9053506

ABSTRACT

PURPOSE: The retinoid response is mediated by nuclear receptors, including retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). All-trans retinoic acid (RA) binds only RARs, while 9-cis RA is an agonist for both RARs and RXRs. Recently, LGD1069 was identified as a highly selective RXR agonist with low affinity for RARs. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of LGD1069 in patients with advanced cancer. PATIENTS AND METHODS: Fifty-two patients received. LGD1069 administered orally once daily at doses that ranged from 5 to 500 mg/m2 for 1 to 41 weeks. Treatment proceeded from a starting dose of 5 mg/m2. Pharmacokinetic sampling was performed on selected patients on days 1, 15, and 29. RESULTS: Reversible, asymptomatic increases in liver biochemical tests were the most common dose-limiting adverse effect. Less prominent reactions included leukopenia, hypertriglyceridemia, and hypercalcemia. Characteristic retinoid toxicities, such as cheilitis, headache, and myalgias/arthralgias, were mild or absent. Two patients with cutaneous T-cell lymphoma experienced major antitumor responses. Pharmacokinetic studies obtained in 27 patients at eight dose levels showed that the day 1 area under the plasma concentration-times-time curves (AUCs) were proportional to dose. At all doses studied, the day 1 AUCs were similar to those on days 15 and 29, indicating a lack of induced metabolism. CONCLUSION: LGD1069 is a unique compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor-cell proliferation and apoptosis. Further investigation of this drug is warranted. Based on the results of this study, a dose of 300 mg/m2 is recommended for single-agent trials.


Subject(s)
Anticarcinogenic Agents/pharmacology , Neoplasms/blood , Tetrahydronaphthalenes/pharmacology , Adult , Aged , Aged, 80 and over , Anticarcinogenic Agents/administration & dosage , Anticarcinogenic Agents/adverse effects , Anticarcinogenic Agents/pharmacokinetics , Area Under Curve , Bexarotene , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/adverse effects , Tetrahydronaphthalenes/pharmacokinetics
16.
Invest New Drugs ; 15(3): 227-34, 1997.
Article in English | MEDLINE | ID: mdl-9387045

ABSTRACT

The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11 diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase. These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1 h i.v. infusion every 12 h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search. Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t1/2 of 0.12 h. We conclude that great caution is warranted in administering DENSPM on this schedule at doses of > or = 83 mg/m2/day.


Subject(s)
Antineoplastic Agents/adverse effects , Central Nervous System Diseases/chemically induced , Neoplasms/drug therapy , Spermine/analogs & derivatives , Adenocarcinoma/drug therapy , Adult , Aged , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Biological Availability , Colonic Neoplasms/drug therapy , Female , Half-Life , Humans , Lung Neoplasms/drug therapy , Male , Melanoma/drug therapy , Metabolic Clearance Rate , Middle Aged , Spermine/adverse effects , Spermine/pharmacokinetics
17.
Semin Oncol ; 23(6 Suppl 16): 26-31, 1996 Dec.
Article in English | MEDLINE | ID: mdl-9007117

ABSTRACT

In preparation for the design of phase II studies in lung cancer, low-dose carboplatin, fixed at a target area under the concentration-time curve (AUC) of 4.0 or 4.5 mg x min/mL, has been combined with escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in a series of studies to establish the maximum tolerated dose of the combination. In patients who had received prior chemotherapy, the maximum tolerated paclitaxel dose was 135 mg/m2 (carboplatin target AUC 4.0); the dose-limiting toxicity was febrile neutropenia. Without granulocyte colony-stimulating factor support in chemotherapy-naive patients (carboplatin target AUC 4.5), and with granulocyte colony-stimulating factor in chemotherapy-pretreated patients, the current paclitaxel dose is 290 mg/m2. The maximum tolerated dose has not been defined. In a study in which paclitaxel was given by 1-hour infusion with carboplatin (target AUC 4.5), a 205 mg/m2 dose was poorly tolerated. No evidence of pharmacokinetic interactions between paclitaxel and carboplatin was found. Twenty-one evaluable patients with lung cancer have been treated to date. There have been two partial responses, one minor response, and 10 patients with stable disease at paclitaxel doses of 100 to 270 mg/m2.


Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Paclitaxel/administration & dosage , Antineoplastic Agents, Phytogenic/pharmacokinetics , Antineoplastic Agents, Phytogenic/toxicity , Carboplatin/administration & dosage , Drug Tolerance , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Male , Paclitaxel/pharmacokinetics , Paclitaxel/toxicity , Treatment Outcome
18.
Clin Cancer Res ; 2(4): 669-77, 1996 Apr.
Article in English | MEDLINE | ID: mdl-9816217

ABSTRACT

We aimed to determine the toxicity and immunological effects of daily s.c. administered low-dose interleukin (IL) 2. Adult cancer patients received a single daily s.c. injection of IL-2 as outpatients for 90 consecutive days. Cohorts of four to nine patients were treated at escalating IL-2 dose levels until the maximum tolerated dose (MTD) was defined. Peripheral blood mononuclear cell phenotyping, IL-2 serum levels, and the presence of anti-IL-2 antibodies were investigated. Thirty-eight patients were treated at seven IL-2 dose levels ranging from 0.4 to 1.75 million International Units (mIU)/m2 daily. The MTD was 1.25 mIU/m2, with constitutional side effects, vomiting, and hyperglycemia dose limiting. Severe toxicity did not occur at or below the MTD, although mild local skin reaction and mild constitutional side effects were common. Objective tumor regressions were not observed during this Phase I trial. Low-dose IL-2 resulted in natural killer (NK) cell (CD3(-) CD56(+)) expansion at all dose levels. This effect was dose dependent (P < 0.01), ranging from a 154 to 530% increase over baseline. Peak NK levels were achieved at 6-8 weeks and sustained through 12 weeks of therapy. As predicted by in vitro studies of IL-2 receptor structure-activity relationships, the subset of NK cells that constitutively express high-affinity IL-2 receptors (CD3(-)CD56(bright+)) showed more profound dose-dependent expansion, with increases ranging from 368 to 2763% (P = 0.015). NK expansion occurred at peak IL-2 levels <10 pM (2.3 IU/ml). Three patients developed nonneutralizing anti-IL-2 antibodies. Thus, we concluded that selective expansion of NK cells may be achieved in vivo with daily s.c. injections of low-dose IL-2 with minimal toxicity.


Subject(s)
Interleukin-2/administration & dosage , Killer Cells, Natural/drug effects , Neoplasms/therapy , Adult , Aged , Humans , Injections, Subcutaneous , Interleukin-2/adverse effects , Killer Cells, Natural/immunology , Middle Aged , Neoplasms/immunology
19.
Clin Cancer Res ; 2(3): 471-5, 1996 Mar.
Article in English | MEDLINE | ID: mdl-9816192

ABSTRACT

The retinoid response is mediated by families of nuclear receptors, the retinoic acid receptors (RARs), and the retinoid X receptors. All-trans retinoic acid (RA) binds only RARs and induces its own metabolism. In contrast, 9-cis RA is a newly identified agonist for both RARs and retinoid X receptors. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of 9-cis RA in patients with advanced cancer. Thirty-four patients received once daily p.o. doses of 9-cis RA (administered as LGD1057) ranging from 5 to 230 mg/m2 for 4 weeks. Pharmacokinetic studies were performed on 28 patients at seven dose levels. 9-cis RA was generally well tolerated. Headache was the most common dose-limiting adverse effect. Other prominent reactions included facial flushing, myalgia, dyspnea, hypertriglyceridemia, and hypercalcemia. Relative to other retinoids, mucocutaneous reactions were mild. No major antitumor responses were observed. Pharmacokinetic analysis revealed that the day 1 area under the plasma concentration x time curves (AUCs) were proportional to the dose. Up through doses of 140 mg/m2, the day 1 AUCs were similar to those on days 15 and 29. At higher doses, however, AUCs tended to decline with repeat dosing. 9-cis RA is a novel compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor cell proliferation and differentiation. We recommend a dose of 140 mg/m2 for single-agent trials utilizing a once-daily schedule of administration.


Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Receptors, Retinoic Acid/agonists , Transcription Factors/agonists , Tretinoin/therapeutic use , Adult , Aged , Alitretinoin , Female , Humans , Male , Middle Aged , Retinoid X Receptors , Tretinoin/adverse effects , Tretinoin/pharmacokinetics
20.
Semin Oncol ; 22(5 Suppl 12): 13-6, 1995 Oct.
Article in English | MEDLINE | ID: mdl-7481855

ABSTRACT

An ongoing phase I and pharmacokinetic trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin is evaluating the maximum tolerated dose (MTD) of a 3-hour paclitaxel infusion combined with fixed doses of carboplatin in previously treated and untreated patients with a variety of advanced cancers. A patient's previous treatment status determines the fixed carboplatin dose: target area under the concentration-time curves of 4.0 and 4.5 mg.min/mL in previously treated and untreated patients, respectively. Studies 1 and 2 entered previously treated patients to establish the paclitaxel MTD without and with cytokine support: study 1 established 135 mg/m2 paclitaxel as the MTD without such support. In study 2, granulocyte colony-stimulating factor is administered, and the MTD has not yet been reached with paclitaxel doses of 135 mg/m2 to 230 mg/m2 assessed thus far and 250 mg/m2 now being evaluated. Objective responses have been seen in three of five patients with squamous cell carcinoma of the head and neck and in patients with non-small cell lung cancer and metastatic cancer of unknown primary site as well. Myelosuppression has been the dose-limiting toxicity, although significant nausea and vomiting and myalgia have been documented occasionally. Paclitaxel apparently has nonlinear pharmacokinetics with a beta half-life of 6.7 hours (SD +/- 1.3 hours). Future trials of paclitaxel/carboplatin will address the management of squamous cell carcinoma of the head and neck and non-small cell carcinoma of the lung.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Head and Neck Neoplasms/drug therapy , Paclitaxel/administration & dosage , Adenocarcinoma/drug therapy , Adenocarcinoma/secondary , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carboplatin/administration & dosage , Carcinoma, Bronchogenic/drug therapy , Carcinoma, Squamous Cell/drug therapy , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Half-Life , Humans , Male , Middle Aged , Paclitaxel/adverse effects , Paclitaxel/pharmacokinetics
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