PubMed Health⌕ Search

Biomedical subjects

D Bissett

Publications and source records attributed to D Bissett.

33 records · Page 2Linked to original sources
PubMed1993

Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion.

N-Debenzoyl-N-tert-butoxycarbonyl-10-deacytyl taxol (Taxotere, RP 56976) is a semisynthetic analogue of taxol, prepared from a noncytotoxic precursor extracted from the needles of the European yew tree (Taxus baccata L.). It has a broad spectrum of antitumor activity against a variety of transplantable tumors in mice. In vitro cytotoxicity assays suggest that it is 2-5-fold more potent than taxol. In this phase I study Taxotere was administered by 24 h i.v. infusion at 3-week intervals. Thirty patients with solid tumors refractory to conventional therapy were treated; 70 courses of Taxotere were administered at doses ranging from 10 to 90 mg/m2. Grade 4 neutropenia and grade 3 mucositis were dose limiting but reversible at 90 mg/m2. The pattern and grade of toxicity at this dose were similar in 3 heavily pretreated patients compared with 7 patients who had received a maximum of one previous chemotherapy regimen. Alopecia occurred at 55 mg/m2 and above. Other mild toxicities included phlebitis, diarrhea, emesis, and sensory peripheral neuropathy, but these were neither dose-limiting nor clearly dose-related. One patient treated at 70 mg/m2 had an anaphylactoid reaction following the second dose of Taxotere. No cardiovascular toxicity was observed. No partial or complete responses were documented. Plasma concentrations of Taxotere were determined by high-performance liquid chromatography, and end-of-fusion levels at the maximum tolerated dose exceeded drug concentrations which are cytotoxic in vitro. The maximum tolerated dose for Taxotere administered as a 24-h infusion is 90 mg/m2.

Adult↗
PubMed1993

Cisplatin-DNA damage recognition proteins in human tumour extracts.

Enhanced repair of DNA adducts may be a cause of cis-diamminedichloroplatinum(II) resistance in solid malignancies. Binding of specific damage recognition proteins to the sites of DNA damage may be involved in the initial steps of DNA repair, or alternatively may block access of repair proteins to damaged DNA. Proteins which bind specifically to CDDP-modified DNA were identified in cell extracts from human ovarian carcinoma cell lines by two assays, the gel mobility shift assay and the southwestern blot. In the first assay, proteins complexed with CDDP-modified oligonucleotide and produced two retarded bands, B1 and B2. The B2 complex was partially purified from an ovarian cell extract by anion exchange FPLC, and was shown to bind to DNA damaged by CDDP but not by transDDP or UV irradiation. Using the southwestern blot, proteins of 97, 48, and 25 kD were identified; each of these bound to CDDP-modified but not undamaged oligonucleotide. The partially purified B2 protein fraction contained both the 97 and the 25 kD damage recognition proteins. A human ovarian carcinoma cell line selected in vitro for CDDP-resistance (OV1P/DDP), which is 5-fold more resistant to CDDP than the parental line (OV1P), showed an increase in binding of the 97 and 48 kD damage recognition proteins compared with the parental line. Twelve ovarian cell lines differed by up to 3-fold in their expression of these proteins, but there was no correlation between the amount of damage recognition protein in a cell extract and the cellular sensitivity to CDDP. Damage recognition proteins were also demonstrated in extracts prepared from biopsies of human ovarian, cervical, and testicular malignancies, but there was no apparent difference in the binding activity in extracts from tumours of different CDDP-sensitivity. The functional role of these damage recognition proteins remains to be established.

Base Sequence↗
PubMed1992

Phase I and pharmacokinetic study of rhizoxin.

Rhizoxin is a tubulin-binding cytotoxic compound, isolated from the fungus Rhizopus chinensis, with significant antineoplastic activity in several murine and human tumor models. In this Phase I study, the drug was administered by i.v. bolus injection at 3-wk intervals. Twenty-four patients with refractory solid tumors were treated; 60 courses of rhizoxin were given, at doses ranging from 0.8 to 2.6 mg/m2. Grade 3 mucositis, Grade 4 leukopenia, and Grade 3 diarrhea were dose limiting but reversible at 2.6 mg/m2, the maximum tolerated dose for both previously untreated and heavily pretreated patients. Alopecia and moderate discomfort at the injection site occurred at all doses. Other sequelae, including peripheral neuropathy, phlebitis, and nausea and vomiting, were sporadic and mild. Two heavily pretreated patients with recurrent breast cancer had minor responses to rhizoxin, one at 1.6 mg/m2 and the other at 2.6 mg/m2. Plasma concentrations of rhizoxin were measured by high-performance liquid chromatography. The drug was not detectable (less than 5 ng/ml) at doses of 0.8 mg/m2 and 1.6 mg/m2 and was not measurable 10 min after injection at 2.0 mg/m2. At 2.6 mg/m2, there was considerable intersubject variation in the plasma concentration-time profiles; the area under the curve ranged from 0.29 to 0.96 microgram/ml.min. Rhizoxin has shown some clinical activity in this Phase I study, and a dose of 2.0 mg/m2 is recommended for Phase II studies using this schedule.

Adult↗
PubMed1992

Preclinical and phase I studies with rhizoxin to apply a pharmacokinetically guided dose-escalation scheme.

BACKGROUND: Rhizoxin is a new macrocyclic lactone isolated from the fungus Rhizopus chinensis which displays broad-spectrum antitumor activity against murine and human tumor xenografts and has activity against a number of vincristine-resistant tumors in vitro and in vivo. PURPOSE: This study describes the preclinical and clinical pharmacology of rhizoxin to apply a pharmacokinetically guided dose-escalation (PGDE) strategy during the phase I trial. METHODS: Rhizoxin was administered by a single intravenous bolus injection to female BALB/c mice over the dose range 7.5-18 mg/m2 from which we derived the dose that was lethal to 10% and 50% of the mice (i.e., LD10 and LD50, respectively). The LD10 was 11.7 +/- 0.7 mg/m2 (mean +/- SD), and the LD50 was 14.7 +/- 0.6 mg/m2. Pharmacokinetic studies were integrated with the toxicity study in female BALB/c mice at one-tenth the LD10, one-half the LD10, and the LD10 (i.e., 1.2, 6, and 12 mg/m2, respectively). From these data, a target area under the plasma drug concentration versus time curve (AUC) (i.e., 40% of the LD10 AUC) was calculated for clinical studies. Phase I studies were initiated at 0.8 mg/m2 (one-tenth the equivalent LD10 in male CD1 mice), with the intent of escalating the dose by an extended factor-of-two method until the target AUC and/or maximum tolerated dose (MTD) was reached. RESULTS: The major drug toxic effects in mice were body weight loss, sluggishness, ataxia, transient changes in hematological parameters, and hematuria. Diarrhea was universal at doses greater than 9 mg/m2, and hind limb paralysis was observed in one of 10 mice, but only at supralethal doses (18 mg/m2). Rhizoxin pharmacokinetics were best described by a two-compartment open model (half-life [t 1/2] alpha = 4.4 minutes +/- 0.9 minute [mean +/- SD], and t 1/2 beta = 84 minutes +/- 20 minutes at 12 mg/m2) and found to be nonlinear with respect to dose. At doses of 1.2, 6, and 12 mg/m2, the respective AUC values were 1.3, 22.4, and 70.6 microM x minute. From these data, a target AUC value of 28 microM x minute (40% of the LD10 AUC) was derived. Rhizoxin was not detectable in patient plasma (less than 5 ng/mL at 0.8 and 1.6 mg/m2), and doses had to be escalated by conventional methods. Myelosuppression was dose limiting in patients: Seven of eight treated at 2.6 mg/m2 experienced World Health Organization grade 3-4 neutropenia, and five of eight developed mucositis. The AUC values at the human MTD (2.6 mg/m2) were in the range of 0.41-1.01 microM x minute, considerably lower than the target AUC of 28 microM x minute. CONCLUSION AND IMPLICATIONS: Although PGDE schemes have been successfully employed for other antitumor agents, this methodology could not be applied during the phase I trial of rhizoxin. PGDE studies in the future may incorporate comparative murine versus human metabolism studies in vitro with phenotyped liver microsomes. It may also be useful to assess the comparative myelotoxicity of a new drug by performing in vitro cytotoxicity studies on mouse and human bone marrow stem cells.

Adolescent↗
PubMed1991

The role of palliative radiotherapy in malignant mesothelioma.

Chest pain is often a major problem in patients with malignant pleural mesothelioma but there are few data regarding the usefulness of radiotherapy (RT) in its palliation. Following a recent retrospective report which suggested that wide-field RT frequently affords pain relief in this disease, we prospectively assessed the effect of hemithorax irradiation on pain control. Twenty-two patients with chest pain due to mesothelioma received 30 Gy in 10 daily fractions to the involved hemithorax. The patients' symptoms were assessed before RT, 1 month after RT, and then 2 monthly. Symptoms were graded by the clinician and the patient, and analgesic requirements were noted at each assessment. Performance status and respiratory status were recorded by WHO and MRC criteria respectively. Nineteen assessable patients have been followed for at least 3 months after RT. The treatment was well tolerated, with nausea and vomiting in only 1 patient. Pain control improved in 13/19 patients at 1 month, but 9/12 patients had worsening chest pain at 3 months, and at 5 months pain control had deteriorated in 6/7 patients. Although partial regression of chest wall masses was seen in 5/9 patients, RT did not appear to delay the progression of respiratory symptoms or radiological changes. The median duration of survival after RT was 4 months. Radiotherapy can relieve pain due to malignant pleural mesothelioma but its effect at this dose is short-lived.

Adult↗
PubMed1991

Phase I and pharmacokinetic study of D-verapamil and doxorubicin.

The calcium antagonist verapamil (a mixture of D- and L-racemers) is a potent modulator of the multi-drug resistance phenotype in vitro at a concentration of 6 microM. Clinical studies have shown dose-limiting toxicity of hypotension and heart block when plasma levels approach the concentrations active in vitro. Previous data indicate that the D-isomer is less cardioactive than the L-isomer but they appear to be equipotent in reversing drug resistance in vitro. In an attempt to increase plasma verapamil concentrations, we have treated ten patients (total of 27 courses) with oral D-verapamil (DVPM), 150-300 mg 6 h, and doxorubicin i.v. 70 mg m2 q 3 weeks. Hypotension (supine systolic BP less than 100 mmHg or a fall in systolic BP of greater than 30 mmHg) occurred in 5/6 patients at 1200 mg day DVPM, in 1/5 at 800 mg day, and in 1/5 at 600 mg day. PQ prolongation (greater than 0.23 s) was demonstrated in 2/5 patients at 800 mg day DVPM. Plasma levels of DVPM and its active metabolite norverapamil were measured and, combining these, levels of 3-4 microM were achieved at 1200 mg day DVPM; however this dose is likely to lead to unacceptable toxicity in the outpatient setting. Using an oral outpatient schedule of administration, an appropriate dose of DVPM is 800 mg day. This provides a combined plasma level (for VPM and DVPM) of 2-3 microM. If DVPM is to prove useful as a resistance modulator, it may require to be administered intravenously with careful inpatient monitoring and support.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Long-term sequelae of treatment for testicular germ cell tumours.

Seventy-four patients previously treated in our department for germ cell tumour of the testis underwent a series of tests to determine the frequency of long-term therapeutic complications. All had received cisplatin-based chemotherapy as part of their treatment. There was a significant deterioration in renal function throughout the group. Eighteen (24%) had supine blood pressure greater than systolic 140 mmHg or diastolic 90 mmHg after treatment but hypertension did not correlate with renal impairment. Raynaud's phenomenon was common after chemotherapy (26/74) as was persistent sensory neuropathy (23/74). Although 34% had testosterone levels below the normal range, only six patients had a low free testosterone index with one testis still in situ; 18 patients have fathered children after chemotherapy. Approximately half of the patients completed a psychosexual questionnaire and some 30% of them admitted to sexual problems which they attributed to their treatment. Long-term sequelae of cisplatin-based chemotherapy for testicular malignancy are frequent and persistent, and follow-up of these patients should include prospective measurement of changes in blood pressure.

Adolescent↗
PubMed1989

Parotid metastases from carcinoma of the breast.

Two patients are described in whom a parotid metastasis occurred 10 years after initial treatment for carcinoma of the breast. The parotid is a very unusual site of metastasis and in both patients it was only one detectable. Parotidectomy with post-operative radiotherapy is advocated in this situation not only to obtain local tumour control but to exclude a primary parotid tumour.

Adenocarcinoma↗
PubMedDate not supplied

Cefotaxime in the treatment of infections of the skin and skin structure.

In a series of open, noncomparative studies, cefotaxime was given to 360 hospitalized patients with bacterial wound infections such as cellulitis, abscesses, or necrotizing ulcers of the skin or subcutaneous tissues. The drug was administered intramuscularly or intravenously in a mean dosage of 4 g per day (range, 1.4-12.0 g per day) in three or four equal doses for at least five days. Clinical response to therapy could not be evaluated for 100 patients, and bacterologic response could not be evaluated for 145 patients. Clinical response was satisfactory in 93.5% of the 260 patients for whom therapy could be evaluated, and bacterial response was satisfactory in 84% of the 225 patients for whom therapy could be evaluated. These rates of response include both single- and multiple-pathogen infections. There were nine instances of superinfection.

Adolescent↗