Inhibition of human tumour clonogenicity by chlorambucil and its metabolites.
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Carcinoma↗
Biomedical subjects
G E Goodman
Publications and source records attributed to G E Goodman.
HPLC, MS, and pharmacokinetics of melphalan, bisantrene and 13-cis retinoic acid.
High performance liquid chromatographic procedures are described for melphalan, bisantrene, and 13-cis retinoic acid, three important anticancer drugs in various stages of clinical development. The procedures require a rapid and simple sample clean-up followed by a 10-to 20-min chromatographic separation on a reversed-phase C18 column. Precisions are all less than 8% with recoveries greater than 80%. Mass spectrometry confirmation of each drug from patient sample separations is presented to provide unambiguous identification for valid pharmacokinetic parameter determination.
Anthracenes↗
Pharmacokinetics of 13-cis-retinoic acid in patients with advanced cancer.
13-cis-Retinoic acid (13-CRA) is a synthetic analog of vitamin A effective reversing preneoplastic lesions in both humans and animals. To study its physiochemical properties and disposition kinetics, we developed a rapid, sensitive, and precise high-performance liquid chromatography assay for 13-CRA in biological samples. This assay system resulted in a clear separation of 13-CRA from all-trans-retinoic acid and retinol and had a detection limit of 20 ng/ml plasma. Recovery was 89 +/- 6% (S.D.) at equivalent physiological concentrations with a precision of 8%. To study the disposition kinetics in humans, 13 patients received a p.o. bolus of 13-CRA and had blood samples collected at timed intervals. For the 10 patients studied on the first day of 13-CRA administration, the mean time to peak plasma concentration was 222 +/- 102 min. Interpatient peak 13-CRA plasma concentrations were found to be variable, suggesting irregular gastrointestinal absorption. Beta-Phase t 1/2 was approximately 25 hr. The prolonged terminal-phase plasma half-life may represent biliary excretion and enterohepatic circulation.
Adult↗
Surgical restaging of Hodgkin's disease.
Twenty-six patients with Hodgkin's disease were restaged both clinically and surgically within 2 months of completing their planned chemotherapy. Six patients (23%) had surgically proven persisting disease. Patients were divided into three groups: group I--eight patients had normal findings at clinical restaging and all were free of disease at surgery; group 2--13 patients had abnormal findings at clinical restaging, but only two (15%) were surgically documented to have persistent disease; and group 3--five patients had incomplete clinical restaging but, because of initial bulky disease, underwent surgical restaging, which showed that four patients had residual disease. The spleen was the site of persisting disease in all six patients with residual disease; four also had para-aortic nodal involvement. All 20 patients in pathologically documented complete remission remain relapse-free, with a mean followup of 26 months. This is significantly better (P less than 0.001) than the 21% relapse rate for 224 comparable patients in complete remission established by clinical but not surgical restaging. It appears that surgical restaging provides useful prognostic and therapeutic information in selected patients with Hodgkin's disease.
Adolescent↗
Phase I clinical trial f mitoxantrone: a new anthracenedione anticancer drug.
Mitoxantrone, 1,4-dihydroxy-5,8-bis(((2-[(2-hydroxyethyl)amino]ethyl) amino))-9,10-anthracenedione dihydrochloride, a new antitumor agent was evaluated in nine cancer patients as part of a phase I trial. In general, the drug was well tolerated. Leukopenia was the dose-limiting toxic effect. Mild to moderate leukopenia (but not neutropenia or thrombocytopenia) occurred in four of six patients given 4 mg/m2/week after a mean of 2.75 doses (range, 2-4 doses) and in all three patients given 5 mg/m2/week after three doses. Only one patient had mild nausea and vomiting. No patient experienced alopecia or mucositis, and none showed evidence of any cardiac, renal, hepatic, or pulmonary abnormality. Mitoxantrone treatment induced two partial remissions (patients with metastatic squamous cell carcinomas of the hypopharynx and rectum) and one mixed response (patient with gastric carcinoma). For phase II studies the starting dose, when used on a weekly schedule, should be 5 mg/m2 in patients who are known to have adequate bone marrow reserve.
Aged↗
Small cell lung cancer.
Lung cancer is the most common cause of cancer death in the United States, with approximately 135,000 men and women dying each year. While much has been learned about the etiologic risk factors, less progress has been made in therapy. Five-year survival rates remain at less than 10%. However, there has been some progress in the therapy of one histological subtype of lung cancer, small cell lung cancer. Totaling around 20% of lung cancer cases, small cell lung cancer is distinct from the other histologic subtypes in its biologic behavior and responsiveness to therapy. In the 1960s, the median survival for patients with small cell lung cancer was approximately 3 months. With combination chemotherapy and radiotherapy median survivals now range from 1 to 2 years, and there is evidence for a curative potential since approximately 10% of patients who initially present with limited disease survive greater than 2 years. The unique clinical aspects of this histological subtype potentially relate to its underlying cell of origin. This behavior is reflected in the numerous paraneoplastic syndromes that frequently accompany small cell lung cancer. Its propensity for early dissemination have made staging the extent of disease an important part of the clinical evaluation. Since small cell lung cancer is sensitive to both chemotherapy and radiation therapy, there have been multiple clinical trials evaluating drug/radiotherapy combinations. This article will briefly describe the unique aspects of small cell lung cancer as opposed to other histological subtypes of lung cancer and give a overview of the current clinical approach and treatment of this disease.
Carcinoma, Small Cell↗
The effect of long-term beta-carotene and vitamin A administration on serum concentrations of alpha-tocopherol.
Many micronutrients are currently being tested for cancer prevention activity. A short-term study recently suggested that two of these nutrients, beta-carotene and alpha-tocopherol, may have an adverse interaction, with beta-carotene supplementation leading to markedly decreased serum concentrations of alpha-tocopherol. We have analyzed the effect of beta-carotene supplementation on serum concentrations of alpha-tocopherol in 2319 participants enrolled in the Carotene and Retinol Efficacy Trial who have taken beta-carotene and vitamin A for up to 6 years. One thousand thirty-five participants enrolled in two pilot trials to the Carotene and Retinol Efficacy Trial had serum collected at yearly intervals; an additional 1284 recently recruited participants had serum collected at biennial intervals. Using standard high pressure liquid chromatography techniques, with attention to quality control, these samples were analyzed for beta-carotene and alpha-tocopherol. After up to 6 years of supplementation with beta-carotene (30 mg/day) and vitamin A (25,000 international units/day) we found a small but statistically significant increase in the serum concentration of alpha-tocopherol in participants taking the active agents. No evidence of a decrease was found in any of the subpopulations examined. We conclude that long-term supplementation with the combination of beta-carotene and vitamin A does not decrease serum concentrations of alpha-tocopherol. Our long-term trial validates results from several shorter trials conducted by others. The concept of adverse interactions between supplemental micronutrients is important. All cancer prevention trials should closely monitor serum concentrations of micronutrients, as well as the incidence of other significant disease.
Anticarcinogenic Agents↗
The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with asbestos-exposed workers.
Pilot studies are an essential component for major chemoprevention trials. Prior to initiating the multicenter Carotene and Retinol Efficacy Trial to assess the effectiveness of beta-carotene and retinol for preventing lung cancer, we conducted pilot studies in Seattle between 1985 and 1988 in two high risk populations: current and former heavy smokers and asbestos-exposed workers. The Asbestos Workers Pilot Study for the Carotene and Retinol Efficacy Trial demonstrated that recruitment of asbestos-exposed participants with relevant risk factors was feasible from identified sources. We documented negligible toxicity and high adherence with the protocol, schedule, and intervention. Results from the pilot led to extension of the placebo run-in period, changes in the eligibility criteria, improvements in recruitment strategies and scheduling, elimination of stratification by risk factors in randomization, modifications of study vitamin dosage and of side effects monitoring, and refinement of trial design parameters for Carotene and Retinol Efficacy Trial. The Smokers Pilot is reported in the accompanying article (G. E. Goodman et al., Cancer Epidemiol., Biomarkers & Prev., 2: 389-396, 1993).
Aged↗
The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with cigarette smokers.
In preparation for a phase IV lung cancer chemoprevention trial, we conducted a pilot trial of beta-carotene and retinol in high-risk smokers. Eligibility criteria were ages of 50-69 years, a smoking history of at least 20 pack-years, and either being a current smoker or having quit within the past 6 years. Participants were recruited by mailing an interest survey to 29,928 age-selected members of King County Medical Blue Shield. We randomized 1,029 women and men to one of four intervention arms: placebo, retinol, 25,000 international units/day; beta-carotene, 30 mg/day; or retinol plus beta-carotene. Participants were followed for side effects and adherence every 2 months either by a telephone call or a clinic visit. Blood was sampled for retinoid, carotenoid, and liver function analyses annually. beta-carotene and retinol were well tolerated during the follow-up period, which had a median of 1.5 years and a maximum of 3.3 years. Yellowing of the skin was seen in both beta-carotene arms. No differences were seen among arms or over time in incidence or severity of the other 15 monitored symptoms and signs or in serum liver function tests. Adherence was good: 83% of participants remained active on study at 1 year and 75% at 2 years. Serum beta-carotene increased from a prerandomization median concentration of 170 to 2100 ng/ml after 4 months of supplementation, and retinyl palmitate median levels more than tripled.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗