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Biomedical subjects

D J Kerr

Publications and source records attributed to D J Kerr.

At least 109 records · Page 6Linked to original sources
PubMed1995

Phase II trials of rhizoxin in advanced ovarian, colorectal and renal cancer.

Rhizoxin is a tubulin-binding anti-neoplastic agent which is active in a range of murine tumour models. The recommended schedule, of intravenous (i.v.) bolus administration at a dose of 2 mg m-2 every 3 weeks, has been assessed in three phase II trials of ovarian, renal and colorectal cancer. In general terms the drug was fairly well tolerated, but the response rate was disappointing: 0/18, colorectal cancer; 0/18, renal cancer; 1 partial response (PR)/17, ovarian cancer.

Adult↗
PubMed1995

Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil.

PURPOSE: A phase I and pharmacokinetic trial was performed between October 1993 and June 1994 to determine the maximum-tolerated dose of hepatic arterial infusion (HAI) of fluorouracil (5-FU) and intravenous (IV) leucovorin (folinic acid; FA) in patients with hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Forty-three patients received 310 courses of HAI chemotherapy administered over 48 hours every 2 weeks. The regimen consisted of FA 200 mg/m2 by IV infusion over 2 hours, followed by a loading dose of 5-FU 400 mg/m2 by HAI over 15 minutes, followed by a 22-hour infusion of 5-FU at doses ranging from 0.8 to 1.84 g/m2, with identical chemotherapy on day 2. Pharmacokinetic studies were performed to determine peak and steady-state plasma concentrations (Css) of 5-FU. RESULTS: Severe diarrhea and cardiac and neurologic toxicity were dose-limiting at 1.84 g/m2. The recommended dose for the 22-hour component of the schedule was 1.6 g/m2 and was associated with tolerable toxicity. A Css of 2.2 +/- 0.8 mumol/L for 5-FU was achieved on the recommended schedule, which compares favorably with conventional IV 5-FU regimens. Among 30 patients assessable for response, there were four complete responses and seven partial responses, and 12 patients with stable disease and seven with progressive disease, reported after 3 months (ie, six cycles) of therapy. CONCLUSION: A regimen that combines 5-FU and FA has been identified for regional chemotherapy in patients with hepatic metastases from colorectal cancer. The systemic levels of 5-FU achieved are similar to the conventional IV de Gramont regimen using an identical schedule of 5-FU and FA, which implies that this chemotherapy has the best of both worlds, ie, a regional advantage in delivering high drug concentrations to the target organ with adequate systemic cover for extrahepatic micrometastases.

Adult↗
PubMed1995

Hemangioblastoma of the optic nerve: case report.

An optic nerve hemangioblastoma arising in the optic nerve of a patient with von Hippel-Lindau syndrome is reported. This represents the 10th published example of a hemangioblastoma arising at this site, the second description of the magnetic resonance imaging features of a hemangioblastoma at this location, and the second patient from whom an optic nerve hemangioblastoma has been removed with the goal of preserving the optic nerve as well as vision. A majority of these optic nerve hemangioblastomas have arisen in patients with von Hippel-Lindau syndrome. All patients experienced progressive loss of vision either to blindness or surgical intervention, although a vast majority of the lesions were sharply demarcated from the adjacent nerve and, thus, potentially resectable. Optic nerve hemangioblastomas are a rare cause of blindness but potentially preventable when treated with a conservative surgical approach aided by neuroimaging guidance. The recognition of discordance between the degree of vision loss and the extent or progression of a retinal hemangioblastoma may be an important clue to diagnosis in the patient with von Hippel-Lindau syndrome.

Adult↗
PubMed1994

Dexniguldipine-HCl is a potent allosteric inhibitor of [3H]vinblastine binding to P-glycoprotein of CCRF ADR 5000 cells.

Cell membranes were prepared from the multidrug resistant, P-glycoprotein expressing human lymphoblastoid cell line CCRF-ADR 5000. The P-glycoprotein of these membranes possessed high affinity binding sites for [3H]vinblastine, with a Kd of 8 +/- 2 nM and Bmax of 17 +/- 8 pmol/mg of protein. The binding of [3H]vinblastine to P-glycoprotein was not ATP-dependent, and was inhibited by cytotoxic drugs with the following potency order; vincristine > doxorubicin > etoposide. The 1,4-dihydropyridine and multidrug resistance reversing agent, dexniguldipine-HCl, inhibited binding with a Ki value of 37 nM. The multidrug resistance reversing agent cyclosporin A, and the cytotoxics doxorubicin and etoposide did not alter the kinetics of [3H]vinblastine dissociation from P-glycoprotein; however, the 1,4-dihydropyridines dexniguldipine-HCl and nicardipine accelerated dissociation of [3H]vinblastine. These data suggest that P-glycoprotein possesses at least two allosterically coupled drug acceptor sites; receptor site 1 which binds vinblastine, doxorubucin, etoposide and cyclosporin A, and receptor site 2 which binds dexniguldipine-HCl and other 1,4-dihydropyridines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

A phase I-II study of N-(phosphonacetyl)-L-aspartic acid (PALA) added to 5-fluorouracil and folinic acid in advanced colorectal cancer.

N-(phosphonacetyl)-L-aspartic acid (PALA) inhibits the enzyme L-aspartic acid transcarbamoylase (ATCase) which is important in de novo pyrimidine synthesis. Low dosages of PALA modulate the in vitro activity of 5-fluorouracil (5-FU) and PALA (250 mg/m2) inhibits pyrimidine synthesis in patients. PALA (250 mg/m2 day 1) was combined with an established 5-FU/folinic acid (FA) regimen [FA (200 mg/m2 over 2 h days 2 + 3) and bolus and 22 h infusional 5-FU (300-500 mg/m2 days 2 + 3)] without the need for dose reduction of 5-FU or FA. 35 patients were entered. Treatment was well tolerated; 4/27 patients experienced > or = ECOG grade 3 toxicity at full 5-FU dosage (500 mg/m2 bolus/infusion). However, the response rate in 33 evaluable patients was only 6.1% [95% confidence intervals (C.I.) 0.2-21.8%]. Median response duration was short (4 months, 95% C.I. 3-6 months) and overall median survival was 10 months (95% C.I. 7-16 months). Although PALA (250 mg/m2) can be combined with full dosage 5-FU/FA, the combination has poor activity in colorectal cancer.

Adolescent↗
PubMed1994

A phase II study of regional 5-fluorouracil infusion with intravenous folinic acid for colorectal liver metastases.

Regional chemotherapy, delivered via the hepatic artery, may significantly increase tumour response rates in patients with colorectal liver metastases. However, survival is limited by extrahepatic disease progression. We have developed a novel therapeutic approach for patients with metastases confined to the liver. In order to achieve high local response rates and also inhibit extrahepatic progression, 5-fluorouracil (5-FU) was infused intra-arterially at a dose previously calculated to achieve both high-dose regional therapy and adequate systemic levels. To enhance efficacy further, 5-FU was combined with high-dose systemic folinic acid (FA). Thirty-one patients were evaluated in a phase II study. 5-FU (1.5 g m2) was infused via a surgically implanted hepatic artery catheter over a 24 h period; FA (total 400 mg m-2) was infused intravenously during the initial and final 2 h. Treatments were given weekly for cycles of 6 weeks' duration. To date, median duration of treatment is 6 months and the median follow-up period is 17 months. The overall response rate was 48% with two complete and 13 partial responses. Predicted median time to progression is 8 months. The site of first progression was hepatic in 10 (42%) and extrahepatic in 14 (58%) patients. Seven patients developed local complications; one required emergency surgery. Side-effects were limited to grade 3 toxicity (four patients) or less. Predicted median survival is 19 months. This approach, which is associated with a high response rate and low systemic toxicity, warrants further evaluation. A phase III study is planned.

Adult↗
PubMed1994

Pharmacokinetic study of 5-fluorouracil in a novel dialysate solution: a long-term intraperitoneal treatment approach for advanced colorectal carcinoma.

Five patients with advanced colorectal and gastric carcinoma with peritoneal deposits were treated by continuous weekdays intraperitoneal (i.p.) instillation of 5-fluorouracil (5-FU) 200 mg m-2 day-1 in a novel dialysate solution that ensures maximal exposure of peritoneal areas liable to bear tumours for 24 h. A solution of icodextrin, a glucose polymer, in a 21 twin-bag delivery system allowed a single daily exchange and demonstrated the feasibility of long-term continuous ambulatory treatment with up to 17.4 g of 5-FU, delivered intraperitoneally, in this initial study. During the entire study, there were 235 fluid exchanges or 470 connections and disconnections and no bacterial peritonitis or exit site infection were observed. There was no treatment-associated toxicity worse than WHO grade 2. Drug concentrations in both peritoneal and plasma compartments followed a first-order model with similar half-life value of 1.3 h. 5-FU pharmacokinetic parameters (half-life values, total body clearance, peritoneal clearance and pharmacological advantage of the i.p. route) with this novel icodextrin carrier solution were similar to those obtained in other referenced pharmacokinetic studies with other carrier solutions (dextrose dialysate and lactated Ringer's solutions). This confirms that icodextrin solution is physiologically neutral, drug compatible and allows adequate dwell times with constant fluid balance for long-term continuous intraperitoneal chemotherapy. The pharmacokinetic parameters from this study will be used to design a loading dose infusion schedule in an attempt to maintain steady-state i.p. 5-FU levels in a new multicentre phase I trial.

Colorectal Neoplasms↗
PubMed1994

Hepatic arterial chemotherapy for metastatic colorectal carcinoma.

In this review, the rationale of regional chemotherapy for treatment of hepatic metastases in advanced colorectal carcinoma is discussed. Pharmacokinetic principles and early clinical experience of hepatic arterial drug administration are summarised. The regional advantage of fluoropyrimidine compounds in this setting is well established, and recent evidence suggests that 5-fluorouracil (5-FU) is more efficacious than the analogue 5-fluoro-2'-deoxyuridine (FUDR). However, while significantly higher clinical response rates can be achieved with hepatic arterial infusion (HAI) chemotherapy compared with conventional intravenous drug administration, patient survival benefit is not significantly different. Several novel approaches to overcome the limitations of HAI therapy are currently being explored. These include concomitant use of biodegradable microspheres, which both slow tumour blood flow and enhance tumour drug uptake, and use of vasoactive agents to redistribute arterial blood flow towards tumours. In addition, novel chemotherapeutic agents which exploit unique biological characteristics of hepatic tumours are entering clinical trial.

Colorectal Neoplasms↗
PubMed1994

Phase I clinical trials: adapting methodology to face new challenges.

BACKGROUND: The conventional phase I clinical trial stands as a bridge between the laboratory and the clinic in the development of novel anticancer agents. The purpose of the phase I study is primarily to determine toxicity and to define the maximum tolerated dose of the drug in man. It is assumed for this purpose that dose-response curves for toxicity and efficacy are parallel or, simply expressed, the more pain, the more gain. Novel antineoplastic drugs are being developed that are mechanistically remote from conventional cytotoxic drugs, which have DNA as their predominant target; some of these new agents have, at least in vitro, bell-shaped dose-response curves. CONCLUSION: It is essential that flexible clinical trial methodologies are developed to accommodate new drugs and that attempts are made, when possible, to incorporate pharmacodynamic endpoints in addition to toxicological endpoints.

Antineoplastic Agents↗
PubMed1994

Quinidine as a resistance modulator of epirubicin in advanced breast cancer: mature results of a placebo-controlled randomized trial.

PURPOSE: To evaluate the effect of quinidine, a putative modulator of P-glycoprotein-mediated drug resistance, on the response rate and toxicity profile of epirubicin in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1989 and 1992, 223 eligible patients were randomized in double-blind fashion to receive epirubicin 100 mg/m2 by intravenous (i.v.) bolus and prednisolone 25 mg orally twice daily, along with either placebo or quinidine (250 mg) capsules, taken for 4 days before and 2 days after chemotherapy. Treatment was continued for a maximum of eight courses. RESULTS: Ten eligible patients did not complete the first cycle of treatment. Of the remaining patients, 106 in the placebo arm received 619 courses of treatment, and 107 in the quinidine arm received 612 courses. The median cumulative dose of epirubicin in both arms was 600 mg/m2. The median quinidine level (measured before epirubicin administration in 288 courses) was 5.5 mumol/L; at this concentration, the drug partially reverses anthracycline resistance in multidrug-resistant (MDR) breast carcinoma cells in vitro. There were no statistically significant differences in hematologic or gastrointestinal toxicity between the two arms. The response rate in the placebo arm was 44% (6% complete remission [CR], 38% partial remission [PR]), and in the quinidine arm was 43% (4% CR, 39% PR). Surviving patients have been monitored for a median time of 74 weeks, and there is no significant difference in the overall or progression-free survival between the two arms. The median survival times were 59 weeks for placebo and 47 weeks for quinidine patients. The estimated relative death rate (quinidine/placebo) was 1.2 (P = .247; 95% confidence interval [CI], 0.88 to 1.63). CONCLUSION: Quinidine at this dose does not significantly alter the toxicity profile, response rate, or survival after epirubicin chemotherapy in patients with advanced breast cancer. This may be due to ineffective modulation of P-glycoprotein by quinidine or the lack of expression of mdr-1 in a sufficient proportion of cells in these tumors, or alternative mechanisms underlying resistance to epirubicin.

Adult↗
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

Phase I clinical study of LL-D49194 alpha 1 with retrospective pharmacokinetic investigations in mice and humans. The EORTC ECTG.

LL-D49194 alpha 1 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m2. One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D49194 alpha 1 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.

Aged↗
PubMed1993

Impact of adjuvant chemotherapy in breast cancer on response to tamoxifen at relapse.

A series of 105 patients with operable breast cancer previously entered in the WMOA adjuvant therapy trials were reviewed in order to assess methods of treatment on relapse and subsequent patterns of relapse and survival, related to previous adjuvant therapy. Tamoxifen was the predominant medical therapy offered on relapse. Unexpectedly, analysis of the relapse and survival data for these hormone-treated patients suggested that prior adjuvant therapy negatively influenced response to tamoxifen, with overall survival of treated and control patients being identical. Although not statistically significant, possible explanations of this trend have been explored.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Effect of polyunsaturated fatty acids on the drug sensitivity of human tumour cell lines resistant to either cisplatin or doxorubicin.

Growth of cells in vitro in the presence of fatty acids can alter the membrane composition and hence fluidity and permeability. Exposure of both doxorubicin (2780AD) and cisplatin (2780CP) resistant human ovarian cell lines to non-toxic concentrations of polyunsaturated fatty acids (gamma-linolenic acid and eicosapentaenoic acid) either before or during exposure to the cytotoxic drug did not modulate drug sensitivity. However, the fatty acids were toxic in their own right. Whilst the ovarian cell lines 2780AD and 2780CP showed a small degree of cross resistance to both fatty acids the doxorubicin resistant breast cell line MCF7/Adr was slightly more sensitive than MCF7. When the interactions between the polyunsaturated fatty acids and cytotoxic drugs were analysed by the isobologram method the toxicities were shown to be additive. The combination of polyunsaturated fatty acids and cytotoxic drugs may have clinical potential provided that the normal tissue toxicities of the two treatments are not additive.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Differential interaction of cisplatin with the HIV-1 long terminal repeat in a resistant ovarian carcinoma cell line.

We constructed a recombinant plasmid, pBHIV1, carrying the long terminal repeat (LTR) sequences of HIV-1 linked to the reporter chloramphenicol acetyl transferase (CAT) gene and to the aminoglycoside phosphotransferase (aph) gene as a selectable marker. We have introduced pBHIV1 in a human ovarian cancer cell line A2780 and in a cisplatin resistant variant 2780CP, and obtained stable geneticin resistant A27HIV1-1 and 27CPHIV1-1 cells, respectively. Both transfectant cells expressed CAT activity from the HIV LTR promoter. The response to the anti-neoplastic drug cisplatin was studied on the LTR regulated CAT activity in both cell lines. It was found that cisplatin at 2.5 x 10(-5) M concentration stimulates the expression of CAT by 26-fold from the HIV LTR in A27HIV1-1, but requires a concentration of 5 x 10(-5) M to enhance expression by 4.1-fold in the cisplatin resistant 27CPHIV1-1 cells. Carboplatin, over a range of concentrations (1 x 10(-6) to 1 x 10(-4) M), does not stimulate expression of CAT from the HIV-1 LTR in either of the transfected cells.

Carboplatin↗
PubMed1993

Pharmacokinetic principles of locoregional chemotherapy.

The rationale for regional chemotherapy is based on the premise that certain tumours are confined to compartments within the body for a large part of their natural history and that the dose-response curves for most cytotoxic drugs are steep. If the drug can be introduced locally, then much higher drug concentrations can be achieved at the site of bulk tumour and the prospects of drug induced cytotoxicity enhanced. The general pharmacokinetic principle guiding regional chemotherapy is that the rate of drug clearance from the local compartment (peritoneal and pleural cavities, vascular territories) is smaller than total body clearance, creating a concentration differential in favour of the local compartment harbouring the majority of the cancer. There is good evidence, under certain situations, that pharmacokinetic advantage can translate to clinical advantage.

Antineoplastic Agents↗
PubMed1993

The epidemiology of thyroid carcinoma.

Thyroid cancer is one of the rarest forms of cancer, yet there are wide variations in the degree of malignancy, ranging from the most rapidly fatal to the relatively benign. This is almost entirely dependent on the histological type. Generally speaking, data available on changing trends of incidence and mortality are subject to reservation, dependent on the degree to which they have been influenced by changing diagnostic criteria and the precision of histopathological description. Nevertheless, there is evidence that mortality is slowly decreasing, while incidence is slowly increasing. The purpose of this review is to try to interpret the temporal trends of incidence and mortality rates for thyroid carcinoma in the last 3 decades in light of the problems arising from changes in diagnostic standards and histological classification regarding thyroid neoplasms. Attention is also drawn to the implications, from a public health viewpoint, of the present intensive detection and treatment of occult thyroid carcinomas.

Causality↗