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Biomedical subjects

I Tannock

Publications and source records attributed to I Tannock.

At least 19 recordsLinked to original sources
PubMed2003

Phase II study of troxacitabine (BCH-4556) in patients with advanced and/or metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada-Clinical Trials Group.

PURPOSE: A multi-institution phase II study was undertaken by National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma. PATIENTS AND METHODS: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m2 intravenously, once every 3 weeks. RESULTS: Of the 33 of 35 patients evaluable for response, there were two confirmed partial responses, 21 patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. Eight patients remained stable for more than 6 months, of whom six remain free of progression. The most common drug-related nonhematologic toxicities observed were skin rash (77.1%), hand-foot syndrome (68.6%), alopecia (51.4%), fatigue (51.4%), and nausea (57.1%). Out of a total of 145 cycles of treatment, 98 were given without steroid premedication, whereas 47 cycles were given with steroid premedication. Without premedication, skin rash occurred in 37% of cycles compared with 26% when steroids were given prophylactically. CONCLUSION: Troxacitabine given at a dose of 10 mg/m2 once every 3 weeks was well tolerated in patients with metastatic renal cell cancer, with common toxicities being a moderate to severe granulocytopenia and skin rash. Steroid premedication may reduce the frequency and severity of the skin rash. Our current study suggests that the nucleoside analog troxacitabine may have modest activity against renal cell carcinoma; however, larger studies are required to confirm this.

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PubMed2001

A National Cancer Institute of Canada clinical trials group phase II study of eniluracil (776C85) and oral 5-fluorouracil in patients with advanced squamous cell head and neck cancer.

UNLABELLED: BACKGROUND/PATIENTS AND METHODS: Thirty-two patients with recurrent head and neck cancer (HNC) following radiotherapy and/or surgery were treated with eniluracil (10 mg/m2) and 5-fluorouracil (5-FU) (1 mg/m2) (E5F) orally twice daily for 28 days followed by a seven-day treatment free period. Thirty-five-day cycles were repeated until disease progression, unacceptable toxicity or patient refusal. Doses were modified for toxicity. Standard toxicity and response criteria were used. RESULTS: Thirty-two patients were accrued; thirty-two and twenty-eight patients were evaluable for toxicity and response, respectively. Twelve patients received three or more cycles of E5F. Drug related toxicities were usually grade 1-2 intensity and included lethargy, nausea or diarrhea (> or = 25% of patients), and anorexia, rash or itch, stomatitis or vomiting (12%-24% of patients). Hematologic toxicity was generally mild; two patients experienced grade 3-5 leukopenia or thrombocytopenia. No significant biochemical toxicity was seen. One patient was withdrawn (severe nausea and vomiting) and one patient died because of drug related toxicity (thrombocytopenia). In the final analysis there were one complete and four partial responses for a 15.6% overall response. CONCLUSIONS: E5F demonstrates activity in chemotherapy naïve patients with advanced HNC cancer with acceptable toxicity profile. Further investigation of E5F with other active agents is warranted in HNC.

Adult↗
PubMed1997

Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.

PURPOSE: A previously reported randomized intergroup trial demonstrated that combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was superior to single-agent cisplatin in patients with advanced urothelial carcinoma. We conducted a long-term analysis of patients included in the intergroup trial to examine factors associated with long-term survival. PATIENTS AND METHODS: Two-hundred fifty-five assessable patients with urothelial carcinoma were randomized to receive either single-agent cisplatin (70 mg/m2 on day 1) or combination chemotherapy with methotrexate (30 mg/m2 on days 1, 15, and 22), vinblastine (3 mg/m2 on days 2, 15, and 22), doxorubicin (30 mg/m2 on day 2), and cisplatin (70 mg/m2 on day 2). Courses were repeated every 28 days. The association between patient characteristics and survival was assessed using Cox proportional hazards models. RESULTS: With long-term follow-up evaluation, survival in the M-VAC arm continues to be superior to cisplatin (P = .00015, log-rank test). Predictors of survival include performance status, histology, and the presence of liver or bone metastasis. Only 3.7% of the patients randomized to M-VAC are alive and continuously disease-free at 6 years. CONCLUSION: Long-term follow-up evaluation of the intergroup trial confirms that M-VAC is superior to single-agent cisplatin in patients with advanced urothelial carcinoma; however, durable progression-free survival is rare. Patients with non-transitional-cell histology, poor performance status, and/or bone or visceral involvement fare poorly and are unlikely to benefit significantly from M-VAC chemotherapy.

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PubMed1996

Pharmacokinetic studies of amiloride and its analogs using reversed-phase high-performance liquid chromatography.

We have studied the pharmacokinetics of amiloride and its analogs. A high-performance liquid chromatographic method has been adapted for the measurement of amiloride, 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and 5-(N, N-hexamethylene)amiloride (HMA) in mouse plasma, kidney, liver and tumor tissues. The method uses a C8 preparative solid-phase column, followed by separation using a reversed-phase C18 column (250 x 4 mm I.D., 5 microns particle size) with detection by ultraviolet absorption at 365 nm. Reversed-phase separations were performed at ambient temperature using a non-linear gradient method with two different mobile phases: mobile phase A was 100% acetonitrile while mobile phase B was 0.15 M perchloric acid at pH 2.20 (flow-rate was 1.2 ml/min). The retention times for amiloride, benzamil (used as an internal standard), EIPA and HMA are 13.4, 19.5, 21.8 and 23.5 min, respectively. The calibration curves are linear over the range of 0.1-50 microM in plasma and in tissues. The half-lives of amiloride, EIPA and HMA (and their confidence intervals) in plasma after intraperitoneal injection of drugs into mice were 68.8 +/- 0.2, 31.2 +/- 2.5 and 39.3 +/- 7.9 min, respectively. Amiloride was detected as a metabolite of EIPA but not of HMA. When EIPA was injected at a dose of 10 micrograms/g body weight, it was cleared rapidly from liver, but concentrations > 1 microM were sustained for at least 2 h in murine kidney and in a transplantable tumor.

Amiloride↗
PubMed1996

Flow cytometric calibration of intracellular pH measurements in viable cells using mixtures of weak acids and bases.

We describe a new method for calibrating intracellular pH (pH1) measurements by flow cytometry, based on the null point method proposed originally by Eisner et al. (Pflügers Arch 413:553-558, 1989). The method involves suspending cells loaded with pH-sensitive dyes, such as SNARF-1 or BCECF, in defined mixtures of the weak acid butyric acid and the weak base trimethylamine. Only the uncharged forms of these agents freely permeate the plasma membrane. The weak acid donates protons intracellularly, whereas the weak base accepts them. In accordance with the Henderson-Hasselbalch equation, when cells are exposed to these mixtures, the steady-state pHi is displaced, and the fluorescence signal reflects this new pHi. The null point method described by Eisner et al. derives pHi by determining the molar ratio of acid to base that produces no change in fluorescence signal. In this paper, we show that it is not necessary to obtain the true null point, because a calibration curve can be derived from "pseudo null" values whose pHi is defined by the equation pHi = pHe -0.5 log [(AT)/(BT)], where pHe is the extracellular pH, and (AT) and (BT) are the total concentrations of weak acid and base in the suspension. We refer to this as the "pseudo null calibration method." It is rapid, technically simple, and reproducible. Compared with the widely used nigericin calibration method, it is not influenced by the intracellular potassium concentration; therefore, it may give a more reliable estimate of the absolute value of pHi.

Acid-Base Equilibrium↗
PubMed1993

Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity.

Solid tumors have been observed to develop an acidic extracellular environment, which is believed to occur as a result of lactic acid accumulation produced during aerobic and anaerobic glycolysis. Experiments using glycolysis-deficient ras-transfected Chinese hamster lung fibroblasts have been performed to test the hypothesis that lactic acid production within solid tumors is responsible for the development of tumor acidity. The variant cells have defects in glucose transport and in the glycolytic enzyme phosphoglucose isomerase with 1% activity compared to parental cells. Consequently, the in vitro rate of lactic acid production by variant cells was < 4% compared to parental cells. An in vitro correlation between lactic acid production and acidification of exposure medium was observed for parental and variant cells. Implantation of both cell lines into nude mice led to tumors with minimal difference in growth rate. As expected, variant cells died when exposed to hypoxic conditions in culture, and parental tumors were observed to have a larger fraction of cells resistant to radiation due to hypoxia (27%) than variant tumors (2%). Using pH microelectrodes, parental (n = 12) and variant (n = 12) tumors were observed to have extracellular pH (pHe) values of 6.65 +/- 0.07 and 6.78 +/- 0.04 (mean +/- SE, P = 0.13), respectively, whereas normal muscle had a pHe of 7.29 +/- 0.06 (P < 0.0001 for both cell lines). The lactic acid content of variant tumors was found to be similar to that in serum, whereas parental tumors had lactic acid content that was higher than in serum (P < 0.0001). We conclude that there was no correlation between lactic acid content and acidosis for these tumors derived from ras-transfected fibroblasts. These results provide evidence that the production of lactic acid via glycolysis is not the only mechanism responsible for the development of an acidic environment within solid tumors.

Aerobiosis↗
PubMed1993

Goals of palliative cancer therapy.

The major conclusions of the Workshop on Goals of Palliative Cancer Therapy are as follows: 1. The goals of any cancer therapy should be stated explicitly. 2. If the goal of treatment is palliation, this should be documented according to one of the established and validated methods for assessment of quality of life. Several validated methods are available, and although imperfect, have been shown to give reliable information. 3. The use of simple measures of quality of life (eg, symptom checklists, pain assessment cards) should become routine in oncology practice. The act of introducing such measures improves palliation. 4. Measures of cost-effectiveness should be used more widely in clinical decision making to ensure the appropriate deployment of resources. 5. There must be improved education of all health professionals with regard to the multiple methods for provision of palliative treatment to cancer patients and the assessment of palliation.

Cost-Benefit Analysis↗
PubMed1992

Effects of agents which inhibit the regulation of intracellular pH on murine solid tumours.

Cell killing can be achieved in an acidic environment in tissue culture (medium pH less than 7.0) by agents (nigericin, carbonylcyanide-3-chlorophenylhydrazone (CCCP)) which transport protons from the extracellular space into the cytoplasm. Cell killing is enhanced when these agents are used in combination with compounds (amiloride, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)) which inhibit the membrane-based exchangers responsible for the regulation of intracellular pH (pHi). We describe experiments which assess the ability of these agents to kill tumour cells in spheroids and in vivo. Both nigericin and CCCP were observed to penetrate tissue based on their ability to kill tumour cells in spheroids. The mean extracellular pH (pHe) of the KHT fibrosarcoma and the EMT-6 sarcoma were observed to be 0.21 and 0.32 pH units more acidic than the mean pHe in muscle tissue. Intraperitoneal (i.p.) administration of the vasodilator hydralazine (10 mg kg-1) caused a reduction of the mean pHe of the KHT but not the EMT-6 tumour. Nigericin (2.5 mg kg-1, i.p.) plus amiloride (10 mg kg-1, i.p.) followed 30 min later by hydralazine (10 mg kg-1, i.p.) reduced the surviving fraction of cells in the KHT and EMT-6 tumours, but had minimal effects on growth delay. When KHT tumours were treated with 15 Gy X-rays followed immediately by nigericin plus amiloride and hydralazine a reduced surviving fraction as well as an increase in tumour growth delay was observed compared to radiation alone. The administration of nigericin (2.5 mg kg-1, i.p.) or the combination of nigericin (2.5 mg kg-1, i.p.) followed by hydralazine (10 mg kg-1, intravenous (i.v.)) resulted in reductions of tumour pHi of 0.27 and 0.29 pH units respectively as determined by 31P magnetic resonance spectroscopy (MRS). Our results show that the combination of nigericin and hydralazine (with or without amiloride) can kill cells in rodent solid tumours and that cell killing is associated with a reduction in the mean pHi of tumour cells.

Amiloride↗
PubMed1992

A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.

PURPOSE: A prospective randomized trial was performed to determine if the addition of methotrexate, vinblastine, and doxorubicin to cisplatin (M-VAC) imparted a response rate or a survival advantage over single-agent cisplatin in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: From October 1984 through May 1989, 269 patients with advanced urothelial carcinoma were entered onto this international intergroup trial and randomized to receive intravenous (IV) cisplatin (70 mg/m2) alone or with methotrexate (30 mg/m2 on days 1, 15, 22), vinblastine (3 mg/m2 on days 2, 15, 22) plus doxorubicin (30 mg/m2 on day 2). Cycles were repeated every 28 days until tumor progression or a maximum of six cycles. There were 246 fully assessable patients of whom 126 were randomized to cisplatin alone and 120 were randomized to the M-VAC regimen. RESULTS: As expected, the M-VAC regimen was associated with a greater toxicity, especially leukopenia, mucositis, granulocytopenic fever, and drug-related mortality. Response rates were superior for the M-VAC regimen compared with single-agent cisplatin (39% v 12%; P less than .0001). Similarly, the progression-free survival (10.0 v 4.3 months) and overall survival (12.5 v 8.2 months) were significantly greater for the combined therapy arm. CONCLUSION: Although a more toxic regimen, we found M-VAC to be superior to single-agent cisplatin with respect to response rate, duration of remission, and overall survival in patients with advanced urothelial carcinoma.

Adult↗
PubMed1991

Chemotherapy for recurrent or metastatic carcinoma of the nasopharynx. A review of the Princess Margaret Hospital experience.

There is little information about the ability of chemotherapy to achieve palliation for patients with recurrent or metastatic carcinoma of the nasopharynx. Therefore, the authors reviewed the records of all patients who had received chemotherapy for this disease at the Princess Margaret Hospital between 1970 and 1989. Seventy patients were identified who had measurable disease and had not received prior systemic therapy. Forty patients received single agents or nonaggressive drug combinations, most of them before 1980. There were three complete responses (CR) and seven partial responses (PR) among this group for a response rate of 25% (95% confidence limits, 13% to 41%). Thirty patients received either drug combinations that were active in aggressive lymphomas or cisplatin-based combinations. There were 7 CR and 14 PR among this group for a response rate of 70% (95% confidence limits, 51% to 85%). Two patients who were treated aggressively are still alive and in complete remission at 3 and 12 years. This type of retrospective review cannot exclude bias caused by patient selection. However, in the absence of randomized trials, the authors suggest the following: (1) carcinoma of the nasopharynx should be considered a malignant neoplasm that is distinct from squamous cell cancer in other sites of the head and neck; and (2) selected patients with recurrent or metastatic carcinoma of the nasopharynx should receive aggressive combination chemotherapy.

Adolescent↗
PubMed1991

How American oncologists treat breast cancer: an assessment of the influence of clinical trials.

The present study was designed to assess the preferred methods of treatment of breast cancer by American oncologists, and the impact of clinical trials on their practice. We mailed 465 questionnaires to surgical, radiation, or medical oncologists. The questionnaire described five hypothetic patients with breast cancer, and respondents were asked to select their preferred treatment for each patient. For primary breast cancer, most physicians would offer the choice of local excision followed by radiation therapy or modified radical mastectomy. About 80% of physicians would prescribe adjuvant chemotherapy for a premenopausal woman with estrogen receptor-negative, axillary node negative breast cancer, and for a postmenopausal woman with estrogen receptor-negative, node-positive disease. This policy was favored by male and female physicians of each specialty. Almost all respondents would treat a young woman with inflammatory breast cancer with initial chemotherapy followed by radiation and/or surgery, and about 60% would recommend chemotherapy to a postmenopausal patient with estrogen receptor-negative disease and minimally symptomatic bone metastases. Clinical trials have compared treatment strategies that could be applied to patients described in our questionnaire. Preferred treatments for primary breast cancer, and for inflammatory breast cancer are supported by the results of clinical trials. Recommendation of adjuvant chemotherapy for node-negative breast cancer is not based on a consistent demonstration of improvement in survival, although randomized trials with short follow-up have shown delay to recurrence. Recommendation of adjuvant chemotherapy for a postmenopausal woman with node-positive breast cancer is contrary to the results of large randomized controlled trials (and to a meta-analysis), which have shown that this policy does not lead to improved survival. Our report suggests that even large randomized clinical trials may have a minimal impact on practice if their results run counter to belief in the value of the treatment.

Adult↗
PubMed1989

Requirement of the Na+/H+ exchanger for tumor growth.

The Na+/H+ exchanger is involved in a variety of cellular processes, including regulation of intracellular pH and possibly the control of cell growth and proliferation. To study the role of the Na+/H+ exchanger in tumor growth, human sodium proton exchanger-deficient (HSPD) mutants were derived from the human bladder carcinoma cell line MGH-U1 (EJ) by the proton suicide selection technique (J. Pouyssegur et al., Proc. Natl. Acad. Sci. USA, 81: 4833-4837, 1984). The HSPD cells were approximately 40% larger and contained approximately 70% more DNA than the parental cells. They were unable to grow in vitro in the absence of bicarbonate at pH less than 7.0, whereas the parental cells grew well at pH greater than or equal to 6.6. This difference in acid sensitivity was abolished in the presence of bicarbonate. In contrast to the parental MGH-U1 cells, the Na+/H+-deficient HSPD cells either failed to grow tumors, or showed severely retarded tumor growth when implanted into immune-deprived mice. This difference in tumor growth was not attributed to differences in cell size and DNA content, because Na+/H+ exchange-competent large cells (HLC), derived during the same proton suicide selection process as the HSPD cells, grew tumors at a rate close to that of the parental cells. Cells derived from the few tumors which grew after implantation of HSPD mutant cells were revertants which had regained Na+/H+ activity. HSPD cells also failed to form spheroids in culture, and the only spheroid formed consisted of revertant cells which had regained both Na+/H+ exchange activity and tumorigenic capacity. These results suggest that the Na+/H+ exchanger is important for tumor growth.

Animals↗
PubMed1989

M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) chemotherapy for transitional cell carcinoma: the Princess Margaret Hospital experience.

We treated 41 patients with transitional cell carcinoma with methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy. Median patient age was 56 years. Of the patients 33 had either distant metastases or locoregional disease that could not be cured by an operation or radiation. Of these patients 30 had measurable disease and 12 responded (4 complete and 8 partial responses, response rate 40 per cent, 95 per cent confidence limits 23 to 59 per cent). Only 2 of these patients remain with an unmaintained complete response at 34 and 52 months. Of 5 patients 3 responded who were treated with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin for locally advanced bladder cancer before radiation or cystectomy, and only 1 of these patients is free of disease. The remaining 3 patients were treated postoperatively because they were at high risk for recurrence and all are well. Toxicity of the regimen was severe: 41 per cent of the patients experienced neutropenic sepsis and 54 per cent required hospitalization for management of toxic complications. Three patients experienced pulmonary embolism and 1 had deep vein thrombosis. There was 1 drug-related death of sepsis. Although a patient occasionally may have long-term benefit from this chemotherapy our results suggest caution in the widespread application of this protocol.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response.

Thirty-seven men with symptomatic bone metastases from prostate cancer that had progressed following earlier treatment with estrogens and/or orchidectomy were treated with low-dose prednisone (7.5 to 10 mg daily). The rationale for this treatment was that some patients might still have hormone-sensitive disease that was stimulated by weak androgens of adrenal origin, and that these androgens could be suppressed by prednisone through its negative feedback on secretion of adrenocorticotrophic hormone (ACTH). Response to treatment was assessed by requirement for analgesics, by the McGill-Melzack pain questionnaire, and by a series of 17 linear analog self-assessment (LASA) scales relating to pain and to various aspects of quality of life. Fourteen patients (38%) had improvement in indices used to assess pain at 1 month after starting prednisone, and seven patients (19%) maintained this improvement for 3 to 30 months (median, 4 months). Reduction in pain was associated with improvement in other dimensions of quality of life, and in the scale for overall well-being. Prednisone treatment led to a decrease in the concentration of serum testosterone in seven of nine patients where it was not initially suppressed below 2 nmol/L, and caused a decrease in serum levels of androstenedione and dehydroepiandrosterone sulfate in more than 50% of patients. Symptomatic response was associated with a decrease in serum concentration of adrenal androgens. We conclude that (1) low-dose prednisone may cause useful relief of pain in some patients with advanced prostatic cancer; (2) relief of pain was associated with suppression of adrenal androgens; and (3) measures of pain and quality of life can be used to assess possible benefits of systemic therapy in patients with metastatic prostate cancer.

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