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Biomedical subjects

D S Alberts

Publications and source records attributed to D S Alberts.

At least 19 recordsLinked to original sources
PubMed1992

Antitumor activity and clinical pharmacology of sulofenur in ovarian cancer.

BACKGROUND: Sulofenur is a diarylsulfonylurea with demonstrated antitumor activity in patients with advanced epithelial ovarian cancer refractory to standard chemotherapy. The dose-limiting toxic effects observed in phase I clinical trials have been anemia and methemoglobinemia, resulting in cyanosis. PURPOSE: The purposes of this study were to further define the response rate, toxic effects, and pharmacokinetics and pharmacodynamics of sulofenur in patients with advanced ovarian cancer. METHODS: We conducted a phase II trial of sulofenur at a dose of 800 mg/m2 per day in 35 patients with stage III or IV ovarian cancer refractory to standard chemotherapy. Pharmacokinetics and pharmacodynamics were analyzed by comparing sulofenur parent and metabolite plasma levels with methemoglobin levels. RESULTS: Partial responses lasting 6.5-18 weeks occurred in four (15%; 95% confidence interval = 4%-35%) of the 26 patients assessable for response. In addition, 42% (11) of the assessable patients had prolonged stable disease (median, 20 weeks). The first nine patients received sulofenur as a daily oral dose for 14 days, with a 21-day treatment cycle. However, they developed substantial anemia and methemoglobinemia. As a result, the next 26 patients received sulofenur daily for 5 days followed by 2 days of rest for 3 consecutive weeks, with a 28-day treatment cycle (5/2-day schedule). Preclinical models predicted that 2 days of rest would decrease toxicity while maintaining antitumor activity. Patients treated with the 5/2-day schedule had relatively less severe anemia and methemoglobinemia and needed fewer red blood cell transfusions (31% versus 78% of patients), but 31% still required dose reductions because of these toxic effects. The hydroxy and keto metabolites of sulofenur had prolonged plasma half-lives relative to the parent compound, and the difference was statistically significant. In addition, the correlations of metabolite concentrations with methemoglobin levels were higher than the correlation of sulofenur concentrations with methemoglobin levels, and those differences were statistically significant. CONCLUSION: We conclude that sulofenur has modest clinical activity in heavily pretreated patients with ovarian cancer. IMPLICATIONS: The toxic effects of anemia and methemoglobinemia may limit the ultimate clinical utility of diarylsulfonylureas until less toxic derivatives with alternate metabolic pathways can be identified.

Adult↗
PubMed1992

Reduction in plasma or skin alpha-tocopherol concentration with long-term oral administration of beta-carotene in humans and mice.

BACKGROUND: Beta-carotene is one of the most commonly used compounds in clinical trials of chemopreventive agents in various neoplastic diseases. Animal studies, including our own, have documented that dietary beta-carotene can reduce plasma alpha-tocopherol (vitamin E) levels, but few published studies have examined the clinical or pharmacokinetic ramifications of long-term, high-dose beta-carotene regimens on other fat-soluble vitamins such as alpha-tocopherol. PURPOSE: This study was designed to determine the effects of long-term beta-carotene supplementation on plasma concentrations of alpha-tocopherol in normal human subjects and in an experimental C3H/HeN mouse model. METHODS: In a double-blind study, 45 normal subjects were randomly assigned to receive 0 (placebo), 15, 30, 45, or 60 mg of oral beta-carotene daily for approximately 9 months. Monthly plasma samples were collected. Thirty-five C3H/HeN mice were fed a basal diet with or without beta-carotene and treated topically with or without alpha-tocopherol, except for the control mice, which received UV radiation for 27 weeks from week 3 to week 30. Plasma and dorsal skin samples were taken after 40 weeks and were analyzed for alpha-tocopherol and/or beta-carotene by high-performance liquid chromatography. RESULTS: Long-term dietary beta-carotene administration resulted in statistically significant reductions in levels of alpha-tocopherol in the skin and plasma of UV-irradiated mice. In the human study, the decrease in plasma alpha-tocopherol levels was progressive and significant between 6 and 9 months of beta-carotene dosing in all dosage groups. The greatest decrease was observed during the 9th (last) month of dosing, with a decrease of 40% from baseline. All oral beta-carotene doses (15-60 mg/d), however, resulted in similar decreases in steady-state plasma levels of alpha-tocopherol and in only small differences in beta-carotene plasma levels. CONCLUSION: Long-term oral administration of beta-carotene decreased steady-state plasma concentrations of alpha-tocopherol. The lack of a significant dose-response effect between doses of beta-carotene and alpha-tocopherol plasma levels is not unexpected, given the small differences in steady-state beta-carotene plasma levels in the four beta-carotene dose groups. IMPLICATIONS: Studies are needed to determine how long-term beta-carotene dosing influences tissue distribution of dietary alpha-tocopherol. Careful surveillance for this and other potentially harmful nutrient interactions should become part of all long-term intervention studies.

Administration, Oral↗
PubMed1992

Primary prevention of colorectal cancer through dietary modification.

Because colorectal cancer is the second leading cause of cancer death in the United States and many developed countries, its primary prevention is of extreme importance. Environmental and dietary factors are considered responsible for 85-90% of all cases. Epidemiologic, animal, and biochemical studies suggest that diets high in total calories and fat and low in various dietary fibers, vegetables, and micronutrients are associated with an increased incidence. Of these factors, calcium and wheat bran have been used most extensively in recent trials. It has been reported that 1.5-2.0 g/day of calcium significantly decreases DNA synthesizing cells of high-risk patients. However, chronic wheat bran supplementation appears to decrease both rectal mucosal DNA synthesis and polyp recurrence. Several clinical trials currently are underway to evaluate the diet-colon cancer link. The results of these studies will help to determine the importance of dietary intervention in the reduction of the colorectal cancer risk.

Animals↗
PubMed1992

Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention.

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest that piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAIDs for chemoprevention of urinary bladder malignancy, there are compelling data which suggest that this should be evaluated. A major effect of NSAIDs is inhibition of cyclooxygenase, the rate-limiting enzyme for conversion of arachidonic acid to important signal molecules, including prostaglandins, which profoundly affect cellular functions in many tissues. The initial enzyme reaction leading to formation of prostaglandin H can be accompanied by cooxidation of xenobiotics resulting in extrahepatic and local tissue production of reactive products which are carcinogenic. The end product prostaglandins, especially prostaglandin E2 (PGE2), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE2 stimulate growth of certain tumor cell lines while inhibition of prostaglandin synthesis with indomethacin or piroxicam can cause suppression. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of G1-to-S phase progression of the cell cycle and a reduction in overall DNA synthesis. It is unclear whether this effect on cell growth results from some direct action of the NSAID or a reduction in prostaglandins or indirectly from modulation of important control signals, such as calcium flux. In addition to cyclooxygenase, NSAIDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP-AMP protein kinases, which may be central to cancer initiation and promotion. NSAIDs can also interfere with transmembrane ion fluxes and with cell-to-cell binding. Prostaglandins can modulate a variety of immunological responses and thereby play an important role in host antitumor immunity. For example, high levels of tissue PGE2 are frequently associated with suppression of immune surveillance and killing of malignant cells. Conversely, immune responses are generally enhanced by drugs that inhibit prostaglandin synthesis. PGE2 can act as a feedback inhibitor for cellular immune processes, such as T-cell proliferation, lymphokine production, and cytotoxicity. This effect is also seen for macrophage activity and natural killer cell toxicity. In general, either increased production of PGE2 or increased sensitivity to normal amounts of PGE2 results in depressed cellular immunity. Cyclooxygenase inhibitors (NSAIDs) such as piroxicam which decrease PGE2 production can stimulate cellular immune function both in vitro and in vivo. A variety of tumor cell lines and human malignancies produce large quantities of prostaglandins.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

A randomized phase II trial of trimetrexate or didemnin B for the treatment of metastatic or recurrent squamous carcinoma of the uterine cervix: a Southwest Oncology Group trial.

Patients with measurable metastatic or recurrent squamous carcinoma of the uterine cervix who had failed prior surgery or radiation therapy were enrolled on this randomized phase II study. Twenty-seven eligible patients were assigned to receive didemnin B at either 2.6 mg/m2 iv every 28 days (sixteen patients) or at 5.6 mg/m2 (eleven patients). Sixteen patients were assigned to receive 12 mg/m2/day iv trimetrexate for 5 days, repeated every 21 days. Toxicity for didemnin B was characterized by nausea and vomiting (78% of patients), anemia (59%), mild diarrhea (11%), and episodic hypersensitivity (three patients). Toxicity for trimetrexate included nausea and vomiting (69%), leukopenia (51%), mild thrombocytopenia (38%), anemia (63%), and diarrhea (31%). No antitumor responses were observed for either agent. Neither trimetrexate nor didemnin B at these doses and schedules is recommended for the treatment of advanced squamous carcinoma of the uterine cervix.

Antineoplastic Agents↗
PubMed1992

Evaluation of amonafide in cervical cancer, phase II. A SWOG study.

The Southwest Oncology Group conducted a Phase II study of amonafide in patients with metastatic or recurrent squamous cell cervical cancer. Twelve of the 15 patients were fully evaluable for response and toxicity. There were no clinical responses seen; 2 patients had stable disease while 13 had progressive disease. The major complication of this therapy was myelosuppression. Four patients had life-threatening granulocytopenia (less than 500/microliters), 3 patients had life-threatening leukopenia (less than 1000/microliters), while 2 patients had life-threatening thrombocytopenia (less than 25,000/microliters). Amonafide has significant toxicity but appears to be an inactive drug in metastatic or recurrent squamous cell cancer of the cervix.

Adenine↗
PubMed1992

A phase II evaluation of esorubicin in ovarian cancer. A Southwest Oncology Group study.

Patients with a pathologically confirmed diagnosis of metastatic or advanced epithelial-type ovarian carcinoma were entered into a Phase II trial of esorubicin. Eligibility criteria included measurable disease; performance status (SWOG) 0-2; no more than one prior chemotherapeutic regimen; and no prior doxorubicin therapy. The starting esorubicin dosing schedule was 30 mg/m2 every 3 weeks for good risk patients and 25 mg/m2 every 3 weeks for poor risk patients. Twenty-one patients were eligible for evaluation of response and toxicity to treatment. These patients received a median of 3 courses of esorubicin (range 1-13 courses). None of the 21 patients experienced a response to esorubicin. Median survival was 5.5 months. Leukopenia was the major toxicity. Eleven (79%) of the good risk patients and 2 (29%) of the poor risk patients experienced severe to life-threatening leukopenia. Mild to severe anemia was seen in 10 (71%) of the good risk patients and 7 (100%) of the poor risk patients. We conclude that esorubicin is ineffective in the treatment of ovarian cancer patients who have received primary chemotherapy.

Aged↗
PubMed1992

Phase I and pharmacokinetic study of 502U83 (an arylmethylaminopropanediol) in cancer patients.

502U83, a novel arylmethylaminopropanediol, has proven active in vivo against a panel of murine leukemia and solid tumors as well as in a tumor clonogenic assay against a variety of fresh human cancers. A total of 35 previously treated cancer patients were enrolled in a phase I study of this compound. The maximally tolerated dose (MTD) appears to be 12,800 mg/m2/72 h by continuous intravenous infusion with severe granulocytopenia occurring in three of five patients. There were no objective clinical responses. Serum pharmacokinetic parameters were as follows: plasma terminal phase half-life (t1/2 beta) = 3.84 h; total body clearance (CLB) = 53.1 l/h/m2; volume of distribution at steady state (Vdss) = 127.9 l/m2; maximum plasma concentration (Cmax) = 3.7 micrograms/ml (at 12,800 mg/m2/72 h dose).

Anthracenes↗
PubMed1979

Cobalt-57 bleomycin for imaging head and neck tumors.

Cobalt-57 bleomycin imaging was performed in 11 patients with a history of head and neck cancer. Clinical and scan findings concurred on the presence and extent of tumor in 9 patients (82%); tumor was present in 7 and absent in 2 of the 9. In 2 patients (18%) the scan demonstrated tumor in the neck but failed to show metastatic sites. Cobalt-57 bleomycin images were of good technical quality, with remarkably low background activity at 24 hours after administration. Cobalt-57 bleomycin imaging appears to be a promising technique for evaluating patients with head and neck tumors.

Adult↗
PubMed1979

Kinetics of intravenous melphalan.

We have studied the disposition and elimination of melphalan after intravenous administration in 9 patients with cancer. High-pressure liquid chromatography and 14C-melphalan were used to assay drug concentration in plasma and urine. Composite plasma t1/2alpha was 7.7 +/- 3.3 and t1/2beta was 108 +/- 20.8 min for 8 of the patients. The mean 24-hr urinary excretion of melphalan was 13.0 +/- 5.4% of the administered dose. In 2 patients, 80% to 100% of the measured 14C counts in plasma and urine samples at each study interval, up to 24 hr after drug administration, could be accounted for by the sum of parent compound, monohydroxy and dihydroxy products, and methanol nonextractable radioactivity (i.e., protein-bound activity). These data and evidence of rapid disappearance from plasma at 37 degrees in vitro suggest that spontaneous degradation, and not enzymatic metabolism, is the major determinant of the t1/2 of melphalan in vivo.

Adult↗
PubMed1979

Oral melphalan kinetics.

The systemic availability of melphalan after oral administration is not well known. Most patients are put on a fixed oral dosage regimen. We have studied the disposition of melphalan in 14 patients after single oral doses. Five were also studied after receiving the same dose intravenously. Oral melphalan had a mean plasma terminal phase half-life (t1/2) of 90 +/- 17 min. The mean area under the plasma concentration:time curve (CXT) was 53 +/- 33 micrograms . min/ml. Urinary excretion of oral melphalan averaged 10.9 +/- 4.9% during the first 24 hr. The CXT ratio (oral:intravenous) for the 5 patients studied after both oral and intravenous melphalal (0.6 mg/kg) ranged between 0.25 and 0.89 and averaged 0.56. After oral dosing in 14 fasting patients, the time at which melphalan first appeared in the plasma varied between 15 min and 6 hr. In a myeloma patient who took oral melphalan, no melphalan was found in plasma or urine up to 24 hr. Some instances of failure of tumor response to oral melphalan may be due to inadequate bioavailability rather than inherent tumor resistance.

Administration, Oral↗
PubMed1979

Combination chemotherapy for alkylator-resistant ovarian carcinoma: a preliminary report of a Southwest Oncology Group trial.

The Southwest Oncology Group has carried out a phase III study of combination chemotherapy in patients with advanced epithelial ovarian cancer who had become resistant to prior drug treatment. Patients previously treated with only alkylating agents were given adriamycin-5-fluorouracil-hexamethylmelamine-cis-dichlorodiammineplatinum(II) combination. There have been 12 partial and two complete responses among 29 evaluable patients (at least one full treatment course) entered in this four-drug combination, for a 48% response rate. Two (7%) additional patients showed objective improvement. The median duration of response was 5.8 months. Ten (34%) of 29 patients have died. The median duration of survival was 12+ months. Patients who had previously received adriamycin plus alkylating agent therapy were treated with 5-fluorouracil-hexamethylmelamine-cis-dichlorodiammineplatinum(II). Only 23 (31%) of these 74 patients have had partial responses while an additional 7% have had objective "improvement"; 27 (36%) of these patients have died. The median duration of survival was 14 months. Both drug regimens were well-tolerated. There were no drug-related deaths. Although thrombocytopenia was dose-limiting in up to 40% of the patients, the mean lowest platelet counts in the four- and three-drug regimens were 116,000 and 123,000/mm3, respectively. There were no cases of serious azotemia (ie, BUN level greater than 40 mg/100 ml) or severe peripheral neuropathy.

Alkylating Agents↗