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Biomedical subjects

J M Ford

Publications and source records attributed to J M Ford.

At least 73 records · Page 4Linked to original sources
PubMed1993

Pharmacologic circumvention of multidrug resistance.

The ability of malignant cells to develop resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of clinical tumors. The phenomenon multidrug resistance (MDR) in cancer cells results in cross-resistance to a broad range of structurally diverse antineoplastic agents, due to outward efflux of cytotoxic substrates by the mdr1 gene product, P-glycoprotein (P-gp). Numerous pharmacologic agents have been identified which inhibit the efflux pump and modulate MDR. The biochemical, cellular and clinical pharmacology of agents used to circumvent MDR is analyzed in terms of their mechanism of action and potential clinical utility. MDR antagonists, termed chemosensitizers, may be grouped into several classes, and include calcium channel blockers, calmodulin antagonists, anthracycline and Vinca alkaloid analogs, cyclosporines, dipyridamole, and other hydrophobic, cationic compounds. Structural features important for chemosensitizer activity have been identified, and a model for the interaction of these drugs with P-gp is proposed. Other possible cellular targets for the reversal of MDR are also discussed, such as protein kinase C. Strategies for the clinical modulation of MDR and trials combining chemosensitizers with chemotherapeutic drugs in humans are reviewed. Several novel approaches for the modulation of MDR are examined.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

N4 to spoken sentences in young and older subjects.

Event-related potentials (ERPs) to spoken sentences were recorded from young and elderly subjects. Sentences ended in semantically typical or atypical words. Subjects listened to the sentences during two attention conditions. In a semantic attention task, subjects listened to the meanings of the sentences for a subsequent memory test. In a phonemic attention task, subjects counted words beginning with the letter "p". Following these tasks, the sentence-final words were presented in isolation. A conventional auditory oddball paradigm was also presented. The N4 components elicited by semantically atypical sentence-final words were slightly attenuated and delayed in the older group. N4 was not influenced by the attention manipulation. Young but not older subjects' N4s were attenuated by repetition. When the sentence-final words were presented a third time in isolation, the N4s elicited were similar in amplitude and latency to those elicited in sentence context, but were not attenuated by repetition. In young and older subjects, the peak amplitude of the sentence-elicited N4 difference wave form was highly correlated with the number of correct recognitions of typical words, but not atypical sentence-final words. In young but not older subjects, sentence-elicited N4 amplitude was correlated with the amplitude of the P3 elicited in the auditory oddball paradigm.

Acoustic Stimulation↗
PubMed1993

Phase II study of carboplatin and adriamycin as second line chemotherapy in small cell lung cancer.

A total of 25 patients with small cell lung cancer (SCLC) were treated with carboplatin and Adriamycin (CA) following symptomatic relapse after initial therapy, or because of static or progressive disease during primary treatment. Nine patients had disease within the thorax, and 16 had extensive metastases at relapse. The overall response rate to CA was 64% (20% complete response: CR; 44% partial response: PR). Survival from presentation in 22 of the patients who have died was 6-36 months (median 13 months), and the median survival from the commencement of CA was 23 weeks (range 1 week-11.5 months). The duration of CR was 4-8 months, and of PR 2-7 months. Hospital admission was required following 12% of cycles for management of the complications of treatment. The increasing use of first line regimens of short duration means that reassessment should be made of the activity of further therapy at relapse.

Adult↗
PubMed1993

Serum concentrations of tacrine hydrochloride predict its adverse effects in Alzheimer's disease.

OBJECTIVE: To assess the value of serum measurements of tacrine hydrochloride and its metabolite in predicting risk of adverse reaction in Alzheimer's disease. METHODS: The study was an outpatient-based controlled clinical trial. Study subjects were 35 female and 31 male patients who were receiving 50 to 150 mg tacrine hydrochloride per day. RESULTS: Serum concentration of tacrine hydrochloride and ratio of tacrine hydrochloride to metabolite were significantly higher in the 45 patients with symptomatic adverse effects (p < 0.001). The tacrine hydrochloride to metabolite ratio was significantly higher (p < 0.05) in the 30 patients in whom abnormal liver function developed, but concentration of tacrine hydrochloride was not significantly higher. Women showed a higher incidence of adverse effects (p < 0.05), and tacrine hydrochloride concentrations were higher (p < 0.05). Tacrine hydrochloride concentration and tacrine hydrochloride to metabolite ratio were higher in both men and women in whom adverse effects developed. CONCLUSION: Tacrine hydrochloride concentration is valuable in predicting the development of adverse effects, and its measurement may improve the use of the drug.

Age Factors↗
PubMed1993

Radiotherapy, hyperthermia, and photodynamic therapy for central nervous system tumors.

This review concentrates on malignant gliomas, with brief mention of cerebral lymphomas, other primary intracranial tumors, and metastases. A recurring theme in the current literature on malignant glioma is the importance of prognostic factors other than treatment in determining outcome. Interesting results are emerging from newer strategies of stereotactic radiotherapy, brachytherapy, and photodynamic therapy, although authors who report these results acknowledge that they have often reviewed patients with intrinsically good prognoses. The year's literature has provided a consolidation of information on prognostic factors, relapse patterns, treatment volume, and dose, providing a basis for future progress.

Astrocytoma↗
PubMed1992

Pharmacokinetics of pamidronate in patients with bone metastases.

BACKGROUND: Pamidronate is a second-generation bisphosphonate used in the treatment of tumor-induced hypercalcemia and in the management of bone metastases from breast cancer, myeloma, or prostate cancer. The pharmacokinetics of pamidronate is unknown in cancer patients. PURPOSE: To determine the influence of the rate of administration and of bone metabolism, we studied the pharmacokinetics of pamidronate at three different infusion rates in 37 patients with bone metastases. METHODS: Three groups of 11-14 patients were given 60 mg pamidronate as an intravenous infusion over a period of 1, 4, or 24 hours. Urine samples were collected in the three groups of patients. Plasma samples were obtained only in the 1-hour infusion group. The assay of pamidronate in plasma and urine was performed by high-performance liquid chromatography with fluorescence detection after the derivatization of pamidronate with fluorescamine. RESULTS: The body retention (BR) at 0-24 hours of pamidronate represented 60%-70% of the administered dose and was not significantly modified by the infusion rate. In particular, the BR at 0-24 hours was not reduced at the fastest infusion rate. Among patients, a threefold variability in BR at 0-24 hours occurred, which was related directly to the number of bone metastases and, to some extent, to creatinine clearance. At 60 mg/hour, the plasma kinetics followed a multiexponential course characterized by a short distribution phase. The mean (+/- SD) half-life of the distribution phase was 0.8 hour (+/- 0.3), the mean (+/- SD) of the area under the curve for drug concentration in plasma x time at 0-24 hours was 22.0 +/- 8.8 mumol/L x hours, and the mean (+/- SD) of the maximum plasma concentration was 9.7 mumol/L (+/- 3.2). Pharmacokinetic variables remained unchanged after repeated infusions applied to four patients. Clinically, the three infusion rates were equally well tolerated without significant toxicity. CONCLUSIONS: The 1-hour infusion rate could be proposed as kinetically appropriate for the administration of pamidronate to patients with metastatic bone diseases.

Aged↗
PubMed1991

Effect of buthionine sulfoximine on toxicity of verapamil and doxorubicin to multidrug resistant cells and to mice.

Resistance of tumor cells to chemotherapeutic drugs may be due to several mechanisms within a single cell line. Resistance to doxorubicin in the human multidrug resistant breast cancer cell line, MCF-7 AdrR, has been attributed to increased glutathione (GSH) S-transferase and GSH peroxidase activity, as well as to increased expression of the mdr1 gene product, P-glycoprotein. We studied the potentiation of doxorubicin activity in these cells by buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, and by verapamil and trans-flupenthixol, agents which interact with P-glycoprotein. Treatment with BSO enhanced the effect of doxorubicin by 1.5-fold, while verapamil or transflupenthixol caused a greater reversal of drug resistance. The combination of BSO with trans-flupenthixol produced no further potentiation of doxorubicin activity. However, the combination of BSO with verapamil and doxorubicin caused up to a 10-fold increment in antiproliferative effect. To explore the mechanism by which BSO interacted with this drug combination, we determined whether or not BSO might potentiate the effects of verapamil. These studies demonstrated that the effects of BSO were predominantly due to an increase in verapamil toxicity rather than to doxorubicin toxicity. In addition, when mice received concentrations of BSO in their drinking water sufficient to deplete GSH and were treated with verapamil, the calcium channel blocker was lethal to 9 of 12 mice receiving BSO compared to 1 of 10 control animals receiving verapamil alone. These studies demonstrate that BSO does not markedly increase the pharmacological effect of doxorubicin against MCF-7 AdrR cells and suggest that alterations in GSH and related enzymes are not a major factor in drug resistance in this cell line. Furthermore, BSO can increase the toxicity of verapamil, a finding which may have important implications for clinical trials.

Animals↗
PubMed1991

Event-related potentials and eyeblink responses in automatic and controlled processing: effects of age.

Seventeen young (mean age = 20.2 years old) and 16 elderly (mean age = 72.6 years old) women were tested with event-related potential (ERP) paradigms designed to elicit responses in reaction time tasks and to a startling noise burst. EEG was analyzed from 17 standard 10-20 electrode sites. Reaction time and performance data suggested that the elderly did not perform worse than the young. Nevertheless, the physiological responses of the elderly differed significantly from those of the young. While the task-dependent P3s at Pz were smaller in the elderly than in the young, the automatic P3 was smaller yet. The distribution of both types of P3 across the scalp was more uniform in the elderly than in the young. Single-trial analyses revealed that the P3 amplitude differences at Pz were not due to latency dispersal of single trials. Single-trial startle eye blink responses to intense noise bursts during the automatic paradigm were considerably less frequent in the elderly, although their individual startle blinks were actually larger. The data demonstrate that the electrophysiological responses of the elderly are different from the young both in tasks eliciting automatic responses and in tasks requiring controlled processing.

Adult↗
PubMed1991

Modulation of resistance to alkylating agents in cancer cell by gossypol enantiomers.

Several cell lines resistant to alkylating agents possess increased activity of glutathione-S-transferase (GST) drug detoxifying enzymes. Inhibition of certain enzymes of the glutathione redox system may affect cellular sensitivity to alkylators. We report that the (-.)enantiomer of gossypol is a potent and selective inhibitor of GST alpha and GST pi isozymes, and that in combination with buthionine sulfoximine (BSO), causes the enhanced modulation of alkylator resistance in two drug resistant cell lines with increased GST activity. The use of (-)gossypol alone had no effect on the 2-5-fold resistance of MCF-7 Adr and Walker resistant cells to chlorambucil, melphalan and BCNU. Cellular depletion of glutathione with BSO resulted in a 2-4-fold modulation of cell sensitivity to these alkylators. However, the combination of (-)gossypol with BSO resulted in a markedly greater modulation of alkylator sensitivity than with either inhibitor alone. Therefore, the complementary inhibition of glutathione and GST by BSO and (-)gossypol, respectively, produced a synergistic modulation of alkylator cytotoxicity in these drug resistant cell lines. The favorable clinical pharmacokinetics of (-)gossypol suggest its further evaluation for use in combination with BSO and alkylating agents in clinical trials.

Alkylating Agents↗
PubMed1991

Event-related potentials in alcoholic men: P3 amplitude reflects family history but not alcohol consumption.

Multilead event-related potentials (ERPs), elicited by auditory and visual stimuli requiring a button press response and by a startling noise requiring no response, were recorded from male alcoholics and age-matched male controls (26-60 years old). Single-trial analyses of blink responses to the startling stimuli indicated that alcoholics startle less frequently but with equivalent amplitude as the controls. In contrast, single-trial analyses of P3 indicated that alcoholics generate a P3 as often as controls, but that their individual P3s are smaller. Alcoholics who reported a positive family history of problem drinking had larger startle blink amplitudes and smaller auditory and visual P3s than did alcoholics who reported a negative family history. Hierarchical regression analysis was used to demonstrate that smaller P3s in family history positive alcoholics were independent of lifetime alcohol consumption.

Adult↗
PubMed1990

Cancer incidence in migrants to New South Wales.

Cancer incidence in migrants to New South Wales (NSW) from the British Isles, north-central, eastern and southern Europe, the Middle East and Asia has been compared with that in Australian-born residents using data from the NSW Central Cancer Registry for 1972-84. Indirectly standardized incidence ratios (SIRs) were low in migrants from all 6 regions for melanoma of skin and cancers of lip and, except in men from eastern Europe, colon. Oesophageal, rectal and prostatic cancers also tended to be relatively less common. Cancers which were more common than in the Australian-born were those of the stomach and, for men, bladder (except in the Asian-born). Migrants from different regions showed variations from the cancer pattern of the Australian-born population which, for the most part, were predictable from the known incidence of cancer in the countries within the region of origin. Exceptions were the high relative incidence of nasopharyngeal cancer in migrants from southern Europe and bladder cancer in men from all regions other than Asia.

Age Factors↗
PubMed1990

Cellular and biochemical characterization of thioxanthenes for reversal of multidrug resistance in human and murine cell lines.

We have previously shown that phenothiazines sensitize multidrug resistant (MDR) cells to chemotherapeutic drugs in a manner related to specific structural features, and have identified structurally related thioxanthenes with increased anti-MDR activity. We have now studied the structure-activity relationships of 16 thioxanthenes in the human breast cancer line MCF-7 AdrR. trans-Thioxanthene stereoisomers were 2- to 7-fold more potent than cis-thioxanthenes for antagonizing MDR. The most potent thioxanthenes possessed a halogenated tricyclic ring connected by a 3-carbon alkyl bridge to a piperazinyl or piperadinyl side group. The chemosensitizing effects of the lead compound, trans-flupenthixol, its stereoisomer cis-flupenthixol, its phenothiazine homologue fluphenazine, and the calcium channel blocker verapamil, were further studied in a series of sensitive and MDR cell lines. trans-Flupenthixol caused a greater reversal of cellular resistance to doxorubicin, vinblastine, vincristine, and colchicine in MCF-7 AdrR, KB-V1, and P388/DOX MDR cells than the other chemosensitizers. In particular, trans-flupenthixol was 2- to 3-fold more potent for reversing MDR than equimolar concentrations of verapamil. Furthermore, trans-flupenthixol fully reversed resistance to doxorubicin, vincristine, and colchicine in MDR MCF-7 and NIH 3T3 cells transfected with the mdr1 gene. None of these agents altered MDR in a non-P-glycoprotein expressing MCF-7 cell line selected with mitoxantrone, nor in any of the parental cell lines. The stereoselective antagonism of the flupenthixol isomers on several putative cellular targets was studied to explore the mechanism of their chemosensitizing activity. cis- and trans-flupenthixol were equally active inhibitors of protein kinase C and calmodulin. Both cis- and trans-flupenthixol were also potent inhibitors of [3H]azidopine binding to P-glycoprotein. The apparent lack of clinical toxicity of trans-flupenthixol makes it an attractive drug for possible use in the modulation of tumor resistance in vivo if appropriate tissue concentrations can be achieved.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Cancer incidence in New Zealand born residents of New South Wales.

Cancer incidence in New Zealand born residents of New South Wales (NSW) has been compared with that in the Australian born population using data from the NSW Central Cancer Registry for the period 1972-84. Indirectly age-standardised incidence ratios (SIR) showed that New Zealand born women living in NSW had higher rates of cancer at all sites combined (SIR = 112) and a significant excess of colorectal cancer (SIR = 126). Although overall cancer rates were similar in men born in New Zealand to those in the Australian born men, the New Zealanders had a significantly higher risk of colorectal (SIR = 124) and testicular cancer (SIR = 227), cancers which are more common in New Zealand than in Australia. While the SIRs for lung cancer in men and melanoma of skin in both sexes were low, no cancer was significantly less common in New Zealand born residents of NSW than in the Australian born.

Colonic Neoplasms↗