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Biomedical subjects

I F Tannock

Publications and source records attributed to I F Tannock.

At least 55 records · Page 3Linked to original sources
PubMed1998

Death of tumor cells after intracellular acidification is dependent on stress-activated protein kinases (SAPK/JNK) pathway activation and cannot be inhibited by Bcl-2 expression or interleukin 1beta-converting enzyme inhibition.

The extracellular microenvironment of tumors differs from that of most normal tissues. Many tumors have relatively acidic extracellular pH, although the intracellular pH of tumor cells remains normal due to the efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms that regulate intracellular pH, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the antiapoptotic gene bcl-2 and its proapoptotic binding partner bax, the stress-activated protein kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. Whereas the expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its proapoptotic function. Inhibition of SAPK, through the expression of a dominant negative mutant of its activator, SEK1, protected cells from acid-induced cell death. Caspase activation, as measured by poly(ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of interleukin 1beta-converting enzyme proteases by the peptide z-Val-Ala-Asp(OMe)-CH2F did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways, but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.

Animals↗
PubMed1998

Measuring health-related quality of life in clinical trials that evaluate the role of chemotherapy in cancer treatment.

Quality of life is a subjective multidimentional concept that can be assessed by means of validated questionnaires completed by patients. The psychological effects of a diagnosis of cancer and the physical effects of the disease and its treating have a major impact on a patient's health-related quality of life. Much cancer treatment, especially chemotherapy for metastatic disease, is given for palliation. Palliation implies improvement in either the duration or quality of life remaining. However, treatment patients with common metastatic tumours to prolong life is generally unsuccessful, so improving quality of life is a more realistic goal. Most trials involve evaluating shrinkage of a tumour (i.e., tumour response), which does not imply a benefit to the patient. Few trials have assessed quality of life directly, although several validated instruments, described here, are available to quantify quality of life in cancer patients. These instruments represent a wide scope, from evaluating general health to assessing the quality of life of patients with specific types and stages of cancer. They respond to changes in clinical state and are strongly predictive of survival. Measures of quality of life should be incorporated in all clinical trials where treatment is palliative, and a simple, relevant measure of quality of life should be used as a (or the) primary outcome measure. Other measures of quality of life are important to ensure that gains in one area do not occur at the expense of others. A few large trials incorporating these principles have shown that chemotherapy can provide palliation for patients with advanced cancer.

Clinical Trials as Topic↗
PubMed1998

Heterogeneity of intracellular pH and of mechanisms that regulate intracellular pH in populations of cultured cells.

Cells within solid tumors are known to exist in a microenvironment that may be acidic and depend on membrane-based mechanisms (Na+/H+ antiport and Na+-dependent Cl-/HCO3- exchanger) that regulate intracellular pH (pHi). We have used the fluorescent pH indicator 2',7'-bis-(2-carboxyethyl) 5 (and 6)-carboxyfluorescein and flow cytometry to study the distribution of pHi and the activity of these pHi-regulating mechanisms among populations of murine mammary sarcoma (EMT6), human breast cancer (MCF-7), and Chinese hamster ovary cells exposed to different levels of extracellular pH (pHe). Cells were exposed to Na+ buffer in the presence or absence of HCO3- and of 5-(N-ethyl-N-isopropyl)-amiloride (a potent inhibitor of the Na+/H+ antiport) to determine the relative importance of each exchanger in the regulation of pHi. Our results indicate that: (a) the distribution of pHi at any value of pHe is broader than can be accounted for by machine noise; (b) cells maintain levels of pHi that are higher than pHe under acidic conditions; (c) the distribution of pHi is narrower when the Na+-dependent Cl-/HCO3- exchanger is active; and (d) populations that are derived from selected cells with values of pHi at lower and higher ends of the pHi distribution generate pHi distributions that are similar to those of controls, suggesting a stochastic variation in the activity of membrane-based mechanisms that regulate pHi. Our data suggest that the Na+-dependent Cl-/HCO3- exchanger is the dominant mechanism for regulation of pHi under moderately acidic conditions such as may occur in the microenvironment of solid tumors.

Amiloride↗
PubMed1998

Responsiveness to change in health-related quality of life in a randomized clinical trial: a comparison of the Prostate Cancer Specific Quality of Life Instrument (PROSQOLI) with analogous scales from the EORTC QLQ-C30 and a trial specific module. European Organization for Research and Treatment of Cancer.

INTRODUCTION: The Prostate Cancer Specific Quality of Life Instrument (PROSQOLI) was developed to be a pragmatic outcome measure for clinical trials in symptomatic men with advanced hormone-resistant prostate cancer. DESIGN AND SETTING: A comparative assessment of responsiveness was made with longitudinal data from a positive multicenter randomized trial of palliative chemotherapy in 161 symptomatic men with advanced hormone-resistant prostate cancer. INSTRUMENTS: The PROSQOLI, the European Organisation for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30), and a specific quality of life module for advanced prostate cancer [QLM-P14] were administered every 3 weeks while patients received their allocated treatment. FINDINGS: Sixteen of the 19 health-related quality of life (HRQL) scales demonstrated improvements in palliative responders. All three pain scales detected a beneficial effect of palliative chemotherapy. The relative efficiency statistics favored the PROSQOLI for physical symptoms and physical function but the QLQ-C30 for emotional function, social function, and global perceptions. The PROSQOLI linear analog scale was the most responsive measure of pain. Bootstrap confidence intervals for the relative efficiency statistics were wide. CONCLUSIONS: Both the PROSQOLI and the analogous scales from the QLQ-C30 were responsive to improvements in HRQL. Differences between the instruments were generally subtle. The PROSQOLI is a short, simple, responsive measure of HRQL in men receiving systemic treatment for advanced hormone-resistant prostate cancer.

Aged↗
PubMed1998

The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase.

Solid tumours develop an acidic extracellular environment with high concentration of lactic acid, and lactic acid produced by glycolysis has been assumed to be the major cause of tumour acidity. Experiments using lactate dehydrogenase (LDH)-deficient ras-transfected Chinese hamster ovarian cells have been undertaken to address directly the hypothesis that lactic acid production is responsible for tumour acidification. The variant cells produce negligible quantities of lactic acid and consume minimal amounts of glucose compared with parental cells. Lactate-producing parental cells acidified lightly-buffered medium but variant cells did not. Tumours derived from parental and variant cells implanted into nude mice were found to have mean values of extracellular pH (pHe) of 7.03 +/- 0.03 and 7.03 +/- 0.05, respectively, both of which were significantly lower than that of normal muscle (pHe = 7.43 +/- 0.03; P < 0.001). Lactic acid concentration in variant tumours (450 +/- 90 microg g(-1) wet weight) was much lower than that in parental tumours (1880 +/- 140 microg/g(-1)) and similar to that in serum (400 +/- 35 microg/g(-1)). These data show discordance between mean levels of pHe and lactate content in tumours; the results support those of Newell et al (1993) and suggest that the production of lactic acid via glycolysis causes acidification of culture medium, but is not the only mechanism, and is probably not the major mechanism responsible for the development of an acidic environment within solid tumours.

Animals↗
PubMed1998

Adjuvant chemotherapy for high-risk urothelial transitional cell carcinoma: the Princess Margaret Hospital experience.

OBJECTIVE: To review the outcome of adjuvant systemic chemotherapy after surgery for patients with locally advanced urothelial transitional cell carcinoma (TCC) of the bladder and upper urinary tract who were at high risk for recurrence or metastatic spread. PATIENTS AND METHODS: Thirty-five patients (27 men and eight women, median age 59 years) received adjuvant chemotherapy and were followed for a median of 31 months from surgery (range 12-109). All patients had undergone surgery (cystectomy, nephrectomy, nephrouretectomy), with removal of all evident tumour from the following primary sites: bladder (29), renal pelvis (three) and ureter (three). Thirty patients had stage pT3 or greater, 22 had node-positive disease and 16 had vascular invasion. The median interval from surgery to chemotherapy was 2 months. Patients received a median of four courses of cisplatin, methotrexate and vinblastine (n = 23) or the same drugs with doxorubicin (n = 12). RESULTS: Toxicity included nine episodes of febrile neutropenia (one fatal) and six episodes of thromboembolism (one fatal). Eighteen patients (51%) remain alive and free of apparent disease with a median follow-up of 31 months. Actuarial overall and relapse-free survival were 64% and 57% at 2 years and 47% and 53% at 5 years, respectively. For the 22 node-positive patients, the median relapse-free survival and overall survival was 22 months and 33 months, respectively. CONCLUSIONS: Patients with urothelial TCC at high risk of relapse after radical surgery can have a reasonable chance of long-term survival with systemic adjuvant chemotherapy. Treatment is associated with toxicity. The benefits of treatment should be addressed in a large randomized controlled trial.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

High risk of vascular events in patients with urothelial transitional cell carcinoma treated with cisplatin based chemotherapy.

PURPOSE: We define the incidence of thromboembolic events in patients receiving multiagent chemotherapy for urothelial cancer. MATERIALS AND METHODS: A retrospective chart review of 271 consecutive patients who received multi-agent cisplatin based chemotherapy for transitional cell carcinoma at Princess Margaret Hospital between 1986 and 1996 was performed. Indications for chemotherapy included adjuvant treatment following resection of high risk disease (13%), and primary management of locally advanced and metastatic disease (87%). RESULTS: Vascular events occurred in 35 patients (12.9%) receiving chemotherapy, including 18 deep vein thromboses, 9 pulmonary emboli, 7 arterial thromboses, 3 cerebrovascular events, 1 superficial phlebitis and 1 angina pectoris (4 patients had deep vein thrombosis and pulmonary embolus). Three events were directly fatal. Overall, 3.6% of chemotherapy cycles were complicated by vascular events with 27 events (77%) occurring during the first 2 cycles. Risk factors for vascular events included a large pelvic mass and concomitant peripheral vascular or coronary artery disease. Substantial morbidity was associated with vascular events and median hospital stay of 10 days. CONCLUSIONS: There is a substantial risk of venous and arterial vascular events in patients receiving cisplatin based chemotherapy for urothelial transitional cell carcinoma. Prophylactic anticoagulation should be considered in patients with risk factors for thromboembolic disease.

Adult↗
PubMed1998

Economic evaluation of chemotherapy with mitoxantrone plus prednisone for symptomatic hormone-resistant prostate cancer: based on a Canadian randomized trial with palliative end points.

PURPOSE: To evaluate the economic consequences of the use of chemotherapy in patients with symptomatic hormone-resistant prostate cancer (HRPC) in the context of a previously published Canadian open-label, phase III, randomized trial with palliative end points. PATIENTS AND METHODS: The trial randomized 161 patients to initial treatment with mitoxantrone and prednisone (M + P) or to prednisone alone (P) and showed better palliation with M + P. There was no significant difference in survival. A detailed retrospective chart review was performed of resources used from randomization until death of 114 of 161 patients enrolled at the three largest centers: these included hospital admissions, outpatient visits, investigations, therapies (which included all chemotherapy and radiation), and palliative care. Cancer center and community hospital costs were calculated by using the hotel approximation method and case costing from the Ontario Case Cost Project, respectively. Cost-utility analysis was performed by transforming the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 global quality-of-life item measured every 3 weeks on trial to an estimate of utility, and extending the last known value through to death or last follow-up. RESULTS: The mean total cost until death or last follow-up by intention-to-treat was M + P CDN $27,300; P CDN $29,000. The 95% confidence intervals on the observed cost difference ranged from a saving of $9,200 for M + P (with palliative benefit) to an increased cost of $5,800 for M + P. The major proportion of cost (M + P 53% v P 66%; CDN $14,500 v $19,100) was for inpatient care. Initial M + P was consistently less expensive in whichever time period was used to compare costs. Cost-utility analysis showed M + P to be the preferred strategy with an upper 95% confidence interval for the incremental cost-utility ratio of CDN $19,700 per quality-adjusted life-year (QALY). CONCLUSION: A treatment that reduces symptoms and improves quality of life has the potential to reduce costs in other areas. Economic factors should not influence the clinical decision as to whether to use M + P in a symptomatic patient.

Canada↗
PubMed1998

Phase I/II study of the CAPABLE regimen for patients with poorly differentiated carcinoma of the nasopharynx.

PURPOSE: To evaluate the role of aggressive combination chemotherapy in patients with poorly differentiated carcinoma of the nasopharynx (NPC). PATIENTS AND METHODS: In a prospective phase I/II study, 90 chemotherapy-naive patients with NPC (21 with very advanced locoregional disease, 18 with locoregional persistent and/or recurrent disease postradiotherapy, and 51 with metastatic disease) were treated with cyclophosphamide, doxorubicin, cisplatin, methotrexate, and bleomycin (CAPABLE). Two schedules of this regimen were used over a 9-year period, with the second schedule being a modification of the first in an attempt to minimize treatment-related toxicity. RESULTS: Of 21 patients with very advanced local disease, one had a complete response (CR) and 17 had partial responses (PRs) (response rate, 86%). Seventeen of these 21 patients had subsequent radiotherapy. Of 17 patients with measurable locoregional disease either persistent and/or recurrent postradiotherapy, there were four CRs and three PRs (response rate, 41%). Of 44 patients with measurable metastatic disease, there were three CRs and 32 PRs (response rate, 80%). The median survival durations for these three groups of patients were 47, 16, and 14 months, respectively. The two chemotherapy schedules had similar received dose-intensities (RDIs) and produced similar response rates and survival. Toxicity was severe with frequent mucositis and myelosuppression. Overall, 37 patients required at least one hospital admission for management of toxic side effects and there were seven drug-related deaths. Three of the deaths were due to fulminant hepatitis, likely from reactivation of hepatitis B. CONCLUSION: This aggressive regimen provides a high rate of tumor response, but limited palliation for most patients with recurrent or metastatic NPC. The results with chemotherapy followed by radiotherapy for patients with very advanced local disease are encouraging, but proof of benefit would require evaluation in a randomized trial.

Adult↗
PubMed1998

Design and interpretation of clinical trials that evaluate agents that may offer protection from the toxic effects of cancer chemotherapy.

PURPOSE: To review the features of randomized clinical trials (RCTs) used in the development of agents that may protect against chemotherapy-induced toxicities, including trials of the cardioprotective agent dexrazoxane, hematologic growth factors, and amifostine; to suggest recommendations based on information gained from such trials and improvements in the design of ongoing and future trials. METHODS: Critical review of reports of RCTs obtained from a Medline search, references from these articles, and review of trials listed in the physician data query (PDQ) clinical trials data base. RESULTS: Several of the phase III trials did not use a format of comparing widely accepted strategies of chemotherapy with and without a protective agent. Instead, patients in the control arms of some of the trials have been exposed to more prolonged use or increased dosage of toxic chemotherapy that placed them at greater risk of the toxicity the protective agent was designed to prevent (eg, cardiotoxicity in trials of dexrazoxane, myelosuppression or thrombocytopenia in trials of growth factors). CONCLUSION: RCTs have shown clear evidence of biologic activity for the protective agents, but this does not imply therapeutic benefit as compared with alternative strategies such as avoidance of prolonged use of cardiotoxic agents or use of standard doses of chemotherapy. Ongoing and future trials of protective agents should be modified to avoid undue risk to patients.

Amifostine↗
PubMed1998

The prognostic role of p53, metallothionein, P-glycoprotein, and MIB-1 in muscle-invasive urothelial transitional cell carcinoma.

Tissue from primary tumors was analyzed for 118 patients with urothelial cancer who subsequently received cisplatin-based chemotherapy. Immunohistochemical staining was performed for nuclear p53 reactivity; for two proposed mediators of drug resistance, metallothionein (MT) and P-glycoprotein; and for the cell proliferation marker MIB-1. For each marker, immunoreactivity was expressed as a percentage of positively staining cells, and overall intensity of staining was graded on a scale from 0 to 3. The product of these two measurements was calculated to generate a percentage-intensity index. Clinical data were obtained independently via retrospective chart review. Chemotherapy regimens containing cisplatin (cisplatin, methotrexate, and vinblastine or methotrexate, vinblastine, doxorubicin, and cisplatin) were administered for metastatic disease (n = 64), for locally advanced disease (n = 45), or as an adjuvant treatment (n = 9). The overall response rate was 56% among 99 evaluable patients, and median survival was 12.7 months. By univariate analysis, Eastern Cooperative Oncology Group performance status (P = 0.0025), tumor grade (P = 0.03), percentage of MT staining (P = 0.01), and percentage-intensity index of MT staining (P = 0.04) were significant predictors of response to chemotherapy. The first three of these were significant in a multivariate model (P = 0.05, 0.04, and 0.04, respectively). By subgroup analysis, the percentage of MT staining predicted for response in metastatic disease (P = 0.03), but not in locally advanced disease (P = 0.28). Only performance status was significantly related to overall survival (P = 0.0001, log-rank test) in the whole cohort. Overexpression of MT in the 64 patients with metastatic disease was associated with a shorter survival (P = 0.04). Expression of p53, P-glycoprotein, and MIB-1 did not predict for survival. In conclusion, overexpression of MT is associated with a poorer outcome from chemotherapy, possibly due to cisplatin resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Influence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecan.

The extracellular pH (pHe) of solid tumours is often lower than in normal tissues, and this may influence the uptake and/or activity of anti-cancer drugs. The cytotoxicity of mitoxantrone, paclitaxel and topotecan was therefore assessed at low pHe and after manipulation of intracellular pH (pHi) in murine EMT6 and in human MGH-U1 cells. The cytotoxic efficacy of all three agents was reduced at pHe 6.5 as compared with pHe 7.4. The ionophore nigericin and inhibitors of membrane-based ion exchange mechanisms that regulate pHi (5-[N-ethyl-N-isopropyl] amiloride, EIPA; 4,4-diisothiocyanstilbene 2,2-disulphonic acid, DIDS) were used to cause intracellular acidification. Combined use of the cytostatic drugs with pHi modifiers reduced their cytotoxicity under both physiological and low-pHe conditions. The uptake into cells of mitoxantrone (a weak base) was inhibited at pHe 6.5 as compared with pHe 7.4, and smaller effects of low pHe to inhibit uptake of topotecan were also observed. DNA analysis of cell cycle distribution revealed that intracellular acidification, as observed during incubation at low pHe and/or using pHi modifiers, resulted in accumulation of cells in G1 phase, where they may be more resistant to these drugs. Reduced uptake of weak bases (mitoxantrone) at low pHe and altered cell cycle kinetics upon acidification are the postulated causes of reduced cytotoxicity of the agents investigated.

Animals↗
PubMed1997

Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer.

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (2',2'-difluorodeoxycytidine) in previously untreated patients with advanced transitional cell carcinoma. PATIENTS AND METHODS: Forty-one patients with measurable advanced transitional cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,200 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed greater than 1 year prior to study entry. All patients were treated on an outpatient basis. RESULTS: There were three complete responses and six partial responses seen in 37 assessable patients, for an overall response rate of nine of 37 (24.3%; 95% confidence interval, 12 to 41). Four patients remain in remission at 14, 23, 24, and 31 months. The median survival was 8 months with 17% of patients alive at 2 years. Treatment generally was well-tolerated with three patients having > or = grade 3 nonhematologic toxicity, five having grade 3 neutropenia, two having grade 3 thrombocytopenia, and two episodes of febrile neutropenia. Most patients were able to receive the drug as scheduled with the primary reason for dose reduction or dose delay being neutropenia. CONCLUSION: Gemcitabine has promising single-agent activity against urothelial cancer with a favorable toxicity profile. Further studies in combination with other active agents are warranted.

Aged↗