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Biomedical subjects

I F Tannock

Publications and source records attributed to I F Tannock.

At least 109 records · Page 6Linked to original sources
PubMed1990

Management of breast and prostate cancer: how does quality of life enter the equation?

Patients with metastatic breast and prostate cancer are not curable. The aim of treatment is palliation, i.e., optimizing quality of life. Unfortunately, this end point has not often been measured. Two recent trials have examined the relationship between intensity of chemotherapy and therapeutic benefit for metastatic breast cancer. Quality of Life as assessed by linear analog self-assessment (LASA) scales was included as a primary endpoint. The trials suggested improved quality of life for standard dose, continuous chemotherapy as compared to reduced dose or intermittent treatment. These results are important in establishing the palliative value of chemotherapy for treatment of metastatic breast cancer. In addition, a series of LASA scales has been developed for assessing quality of life in prostate cancer. Assessment of quality of life should be incorporated in trials of therapy for metastatic breast and prostate cancer.

Breast Neoplasms↗
PubMed1989

Acid pH in tumors and its potential for therapeutic exploitation.

Measurement of pH in tissue has shown that the microenvironment in tumors is generally more acidic than in normal tissues. Major mechanisms which lead to tumor acidity probably include the production of lactic acid and hydrolysis of ATP in hypoxic regions of tumors. Further reduction in pH may be achieved in some tumors by administration of glucose (+/- insulin) and by drugs such as hydralazine which modify the relative blood flow to tumors and normal tissues. Cells have evolved mechanisms for regulating their intracellular pH. The amiloride-sensitive Na+/H+ antiport and the DIDS-sensitive Na+-dependent HCO3-/Cl- exchanger appear to be the major mechanisms for regulating pHi under conditions of acid loading, although additional mechanisms may contribute to acid extrusion. Mitogen-induced initiation of proliferation in some cells is preceded by cytoplasmic alkalinization, usually triggered by stimulation of Na+/H+ exchange; proliferation of other cells can be induced without prior alkalinization. Mutant cells which lack Na+/H+ exchange activity have reduced or absent ability to generate solid tumors; a plausible explanation is the failure of such mutant cells to withstand acidic conditions that are generated during tumor growth. Studies in tissue culture have demonstrated that the combination of hypoxia and acid pHe is toxic to mammalian cells, whereas short exposures to either factor alone are not very toxic. This interaction may contribute to cell death and necrosis in solid tumors. Acidic pH may influence the outcome of tumor therapy. There are rather small effects of pHe on the response of cells to ionizing radiation but acute exposure to acid pHe causes a marked increase in response to hyperthermia; this effect is decreased in cells that are adapted to low pHe. Acidity may have varying effects on the response of cells to conventional anticancer drugs. Ionophores such as nigericin or CCCP cause acid loading of cells in culture and are toxic only at low pHc; this toxicity is enhanced by agents such as amiloride or DIDS which impair mechanisms involved in regulation of pHi. It is suggested that acid conditions in tumors might allow the development of new and relatively specific types of therapy which are directed against mechanisms which regulate pHi under acid conditions.

Animals↗
PubMed1989

Reduction of intracellular pH as a possible mechanism for killing cells in acidic regions of solid tumors: effects of carbonylcyanide-3-chlorophenylhydrazone.

The environment of cells within solid tumors is known to be acidic relative to that in normal tissue, and the viability of tumor cells may depend on mechanisms which maintain intracellular pH (pHi) above the extracellular pH (pHe). We have assessed therefore the toxicity in vitro of the proton ionophore carbonylcyanide-3-chlorophenylhydrazone (CCCP), since this agent has been reported to be capable of transporting H+ equivalent through artificial lipid bilayers and mitochondrial membranes. CCCP was toxic to the human bladder carcinoma cell line MGHU1 and to the murine mammary sarcoma cell line EMT-6 only at pH, less than 6.5. CCCP transported H+ equivalents through cell membranes at physiological (7.35) and low pHc (6.20). Cell lines were found to have steady-state pHi values approximately 0.1 to 0.2 pH units above pHc at pHc less than 6.50. Addition of CCCP led to a decrease in steady-state pHi values as compared to untreated cells at pHc less than 6.50, whereas there was no apparent effect of CCCP on steady-state pHi values at pHc greater than 6.50. The CCCP-induced reduction in steady-state pHi combined with the uncoupling of oxidative phosphorylation by CCCP appeared to be the major mechanisms leading to cell death at pHc less than 6.50. The toxicity of CCCP under acidic conditions was enhanced by amiloride and 4,4'-diisothiocyanostilbene-2,2-disulfonic acid, agents which are known to inhibit membrane-based ion exchange mechanisms which regulate pHi under acidic conditions. When both agents were combined with CCCP, cell killing was observed at pHc less than 7.30. Our results suggest that mechanisms which regulate pHi under acidic conditions which occur in solid tumors may represent targets for new forms of tumor-specific therapy.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1989

Flow cytometric analysis of doxorubicin accumulation in cells from human and rodent cell lines.

The correlation between intracellular accumulation of doxorubicin (DOX) and drug cytotoxicity was studied in cells from seven cell lines of rodent and human origin. We used three Chinese hamster ovary cell lines (AuxB1, CHRC5, and UV20), two murine tumor cell lines (KHT-LP1 and EMT6/Ro), and two human tumor cell lines (MGH-U1 and DLD-1). Intracellular DOX was measured by its fluorescence intensity with flow cytometry, and drug cytotoxicity was quantified with clonogenic assays. When data for all of the cell lines were combined, cell killing was correlated with the intracellular concentration of DOX (r = -.88). For the cell line AuxB1 and its DOX-resistant subline CHRC5, in which cells express high levels of P-glycoprotein, the relationship between cell survival and the intracellular concentration of DOX was stronger than that for the other cell lines. These results suggest that differences in intracellular accumulation of DOX account for much of the heterogeneity in response to the drug in cells from different cell lines, although additional mechanisms also contribute to variation in drug sensitivity. Flow cytometric analysis of intracellular DOX fluorescence is a simple assay that should be tested in cells from human tumors as a possible predictor of tumor response. For a given cell line, this technique also provides a rapid way to monitor the development of drug resistance after multiple courses of chemotherapy.

Animals↗
PubMed1989

Combined modality treatment with radiotherapy and chemotherapy.

Combined modality treatment with radiotherapy and chemotherapy is used increasingly for the primary management of a variety of human tumours, with the aim of improving both local and distant control. The present paper reviews methodological issues related to the evaluation of combined modality therapy. Reports that patients have superior outcome in single-arm studies as compared to historical controls treated with radiation alone have limited value because of several types of bias including patient selection, stage migration, the tendency to publish positive results, or inadequate follow-up as compared to the historical series. The observation that response to chemotherapy predicts for survival after combined treatment also conveys no proof that combined treatment is superior to radiation alone. Randomized controlled trials provide the only rigorous method for evaluating combined therapy, but are also subject to misinterpretation. The majority of published trials report negative results but are too small to detect clinically important differences in survival. Even large trials may give spurious results if they seek small benefits of treatment in a spectrum of patients with widely differing prognosis. Some randomized trials have demonstrated improved local control and increased toxicity from combined treatment, a result that might have been achieved by increasing the effective radiation dose. Ideally, combined treatment should be compared with radiotherapy alone at equal levels of normal tissue damage. A review of published data for patients with cancers of the head and neck, lung, gastrointestinal tract and bladder reveals very few trials which have adequately evaluated the role of combined modality therapy (with or without surgery). Most of the large randomized trials have demonstrated no benefit from the use of radiation and chemotherapy, although some of them suggest small therapeutic gains from using thoracic radiation with chemotherapy in small-cell-lung cancer of limited extent, or from combined modality treatment after resection of rectal cancer. Possible reasons for the failure of active drugs to lead to easily detected gains in therapeutic index include insufficient reduction in cell survival from chemotherapy, selective killing of radiosensitive subpopulations, stimulation of the proliferation of surviving cells, or enhancement of metastasis. With the possible exception of radiation and concurrent 5-fluorouracil for squamous cancers of the anal canal, there are no convincing data to mandate the routine combined use of radiotherapy and chemotherapy in any of the above sites.

Combined Modality Therapy↗
PubMed1988

Malignant properties of sublines selected from a human bladder cancer cell line that contains an activated c-Ha-ras oncogene.

The human bladder cancer cell line MGH-U1 (also designated T-24 or EJ) contains an activated c-Ha-ras oncogene, which is amplified as compared to normal human fibroblasts. We have generated sublines from the MGH-U1 cell line: the MGH-U1/OCI subline was generated by dissociating spheroids formed from MGH-U1 cells; the U1-m/F1 and OCI-m/F1 were generated by in vivo passage of experimental lung metastases formed after i.v. injection of MGH-U1 and MGH-U1/OCI lines into immune-deprived mice; the U1/t subline was generated by in vivo passage of i.m. tumors formed from MGH-U1 cells. All sublines formed tumors in immune-deprived mice from smaller i.m. inocula than the parent line, and the U1-m/F1 subline generated more spontaneous metastases in lungs. Lung colony forming efficiency after i.v. injections of cells into similar mice was also greater for the sublines than for the parent MGH-U1 cells. The U1-m/F1 and OCI-m/F1 were the most tumorigenic lines. Early passages of the MGH-U1/OCI subline showed the presence of double minute chromosomes, and amplification and increased expression of the c-Ha-ras oncogene as compared to the parental cell line. These changes were not present in later cultures of MGH-U1/OCI cells, and no consistent difference in the levels of gene amplification or expression between the parent line and the sublines was found. Thus the content and expression of the activated c-Ha-ras oncogene does not correlate with malignant properties of the sublines.

Animals↗
PubMed1988

Tumour response to chemotherapy in animals that have been treated with the same drugs prior to tumour implantation: a model for studying host effects on apparent drug resistance.

The outcome of cancer chemotherapy is determined by an interplay of multiple factors between the host, the tumour, and the drugs administered. Most studies have emphasised the development or selection of drug resistant tumour cells. However, repeated drug treatment of the host may lead to changes (e.g. in pharmacokinetics, host defences, etc.) which can influence the subsequent response of the tumour. In this study, we present a model to investigate the role of the host in the development of drug resistance. A drug is administered repeatedly to animals prior to tumour implantation, and tumour response is then evaluated following treatment with the same drug in pretreated and control animals. To illustrate the method, cyclophosphamide was administered weekly for 4 weeks to C3H mice before implantation of the KHT tumour. Tumour growth delay was then compared after one further treatment of cyclophosphamide in this group of animals to that in control mice which had not received the cyclophosphamide pretreatment. Our results indicate that cyclophosphamide produces only a small effect on the host in this system, but the model is a potentially useful one to investigate the contribution of the host in the acquisition of drug resistance.

Animals↗
PubMed1988

How expert physicians would wish to be treated if they had genitourinary cancer.

A questionnaire describing six clinical scenarios was mailed to urologists (in Britain, Canada, and the United States) and to radiation and medical oncologists in the United States, who practice genito-urinary (GU) oncology. In each scenario, the surgeon or physician was asked to consider himself as a patient with bladder, prostate, or kidney cancer, and to select his own treatment. Accompanying each scenario were one or two clinical trials for which the physician would be eligible. He was asked to state if he would agree to be randomized in each trial, and if he refused, to state his reasons. We found that (1) there were major differences of opinion about management for each scenario; (2) choice of treatment was influenced more by specialty training or geographic location than by the results of previous clinical trials (which are available to all); (3) British urologists tended to be less aggressive than their North American colleagues, with respect to the use of radical surgery and chemotherapy; (4) acceptance of clinical trials ranged from 3% to 60%; and (5) agreement to clinical trials was quite poor even when they were designed to compare the most popular options for management. This physician surrogate method is a valuable tool in assessment of the degree of consensus amongst expert physicians and in the determination of whether new clinical trials address important areas of controversy.

Adult↗
PubMed1988

A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer.

This study was designed to assess the role of dosage of chemotherapy for treatment of metastatic breast cancer. One hundred thirty-three patients without prior chemotherapy for metastatic disease were randomly allocated to receive two different dose levels of cyclophosphamide (C), methotrexate (M), and fluorouracil (F), administered intravenously (IV) every 3 weeks. Patients were stratified by sites of disease (visceral, bone, or soft-tissue dominant) and by interval from primary surgery to first recurrence. Doses on the higher-dose arm were 600 mg/m2 (C,F) and 40 mg/m2 (M) with escalation if possible; doses on the lower-dose arm were 300 mg/m2 (C,F) and 20 mg/m2 (M) without escalation. Patients who failed to respond to lower-dose CMF were crossed over to the higher-dose arm. Patients randomized to the higher-dose arm had longer survival measured from initiation of chemotherapy (median survival, 15.6 months v 12.8 months, P = .026 by log-rank test), but the effect of dose was of borderline significance (P approximately 0.12) when adjusted for a chance imbalance between the two arms in the time from first relapse to randomization, using the Cox proportional hazards model. Response rates (International Union Against Cancer [UICC] criteria) for patients with measurable disease were higher-dose arm: 16/53 (30%) and lower-dose arm: 6/53 (11%), (P = .03). Only one of 37 patients responded on crossover from the lower- to the higher-dose arm. Patients experienced more vomiting, myelosuppression, conjunctivitis, and alopecia when receiving higher doses of chemotherapy. A series of 34 linear analogue self-assessment scales were used to make detailed quality of life assessments on a subset of 49 patients. These scales confirmed greater toxicity in the immediate posttreatment period, but also a trend to improvement in general health and some disease-related indices, in patients receiving higher-dose chemotherapy. This trial suggests that better palliation is achieved by using full-dose chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Analysis of trials using chemotherapy for metastatic bladder cancer.

Reported rates of tumour response for metastatic bladder cancer vary widely among different institutions, even when similar drug regimens are employed. These differences are due to selection of patients, quality of supportive care, and to methodological differences in the design, analysis and reporting of clinical trials. Because of these factors, intercomparison of response rates from different phase 2 trials is not very meaningful. Trials from the Princess Margaret Hospital have demonstrated palliation from several regimens, but it remains uncertain whether aggressive regimens using several drugs are superior to less toxic chemotherapy. Current clinical trials which randomize patients to receive aggressive chemotherapy or single agents should help to resolve some of these problems.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Toxicity of 5-fluorouracil for aerobic and hypoxic cells in two murine tumours.

Chronically hypoxic cells in solid tumours are reported to be more slowly proliferating than aerobic cells situated closer to blood vessels. Cycle-active drugs such as 5-fluorouracil (5-FU) might be expected to have greater activity against rapidly proliferating aerobic cells. The effect of 5-FU was therefore assessed against aerobic and hypoxic cells in murine tumours; this was done by giving the drug alone or 1 h before irradiation of the tumour under aerobic or hypoxic conditions. Aerobic and hypoxic cells appeared to have equal sensitivity to 5-FU in the KHT and 16/C tumours, and the effect of a single dose of 5-FU was additive to that of radiation.

Aerobiosis↗