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I Tannock

Publications and source records attributed to I Tannock.

At least 37 records · Page 2Linked to original sources
PubMed1989

Analyzing the same data in two ways: a demonstration model to illustrate the reporting and misreporting of clinical trials.

The methods used to analyze and interpret clinical trials of chemotherapy may have a major impact on the conclusions that are drawn in papers reporting them. To illustrate this problem, we constructed a hypothetical clinical trial in which patients with metastatic cancer were treated with chemotherapy. The following two articles provide reports of this trial, analyzed by methods that we would interpret as being of low and high quality, respectively. In the present report, we describe briefly the methodological differences that led to the opposite conclusions based on this single set of data. The errors of reporting and omissions of the first article (A) are similar to those that have been extracted from recent issues of the Journal of Clinical Oncology and other leading cancer journals, although they have not all appeared within a single report. This demonstration model illustrates problems in the reporting of clinical trials and suggests guidelines for improved reporting.

Antineoplastic Agents↗
PubMed1987

Cytotoxicity of compounds that interfere with the regulation of intracellular pH: a potential new class of anticancer drugs.

The extracellular pH (pHe) in many solid tumors is often lower than in normal tissues. Cells may survive conditions of acid pHe because antiports in their membrane exchange Na+ for H+, or HCO3- for Cl-, and thus regulate the intracellular pH (pHi). We have therefore assessed the effects of drugs which interfere with regulation of pHi on survival of Chinese hamster ovary and human bladder cancer MGH-U1 cells in tissue culture. Nigericin, an ionophore which acidifies the cytoplasm when cells are placed in medium at low pHe, was not toxic at pHe 6.5 or above but became very toxic as pHe was reduced below this value. Amiloride and 4,4'-diisothiocyanostilbene 2,2-disulfonic acid, inhibitors of the Na+/H+ and HCO3-/Cl- exchangers, respectively, decreased pHi in the presence of nigericin at low pHe. These drugs showed little or no toxicity in the pHe range of 6.0-7.0 but added greatly to the toxicity of nigericin. A combination of all three drugs led to toxicity in the pHe range of 6.5-6.8, well within the measured range of tumor pH, but not at pHe 7.0 or above. A combination of low pH and hypoxia, two conditions likely to be found in regions distant from tumor blood vessels, caused cell mortality in the absence of drugs, and this effect was increased by nigericin used alone or in combination with amiloride and 4,4'-diisothiocyanostilbene 2,2-disulfonic acid. These drugs may be regarded as prototypes for potential new anticancer agents that might achieve selective killing of tumor cells by interfering with the regulation of intracellular pH.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1987

Sequential chemotherapy and radiation for nasopharyngeal cancer: absence of long-term benefit despite a high rate of tumor response to chemotherapy.

Between April 1981 and December 1983, patients with locoregional carcinoma of the nasopharynx were treated with two courses of chemotherapy administered before radiation therapy. Chemotherapy consisted of methotrexate, bleomycin, and cisplatin, which were administered at 3-week intervals, and radiation therapy was scheduled to commence 3 weeks after the start of the second course. Forty-nine of 51 consecutive patients were treated; only one patient progressed on chemotherapy, and of 36 patients with measurable neck nodes, eight had complete and 19 had partial clearance (greater than 50% decrease in cross-sectional area) of these nodes when assessed before initiation of radiotherapy. Despite the high rate of tumor response (75%; 95% confidence limits, 59% to 91%), the actuarial survival and disease-free survival curves were almost identical to those recorded for a consecutive group of 140 historical controls of similar stage distribution treated with radiation alone. This chemotherapy provided a high rate of tumor remission, but did not appear to convey long-term benefit to patients when used before radiation therapy.

Actuarial Analysis↗
PubMed1986

Methods of immunosuppression for study of growth and lung colony formation by human tumor cells in mice.

Mice that are immune-suppressed by thymectomy and by sequential treatment with 1-beta-D-arabinofuranosylcytosine and whole body irradiation may be used as hosts for generation of human tumor xenografts. We have studied the effect of various additional methods of immune suppression on the formation of tumors after i.m. injection and on the formation of lung colonies after i.v. injection with the human MGH-U1 bladder cancer cell line. Success of transplantation was improved by treatment of immune-suppressed animals with either heterologous antilymphocyte serum or a monoclonal anti-Thy-1.2 antibody. Success of lung colony formation was also improved by antilymphocyte serum but not by monoclonal anti-Thy-1.2 antibody. Admixture of heavily irradiated cells (10(6)) to the viable inoculum of tumor cells in addition to antilymphocyte serum treatment improved the success of i.m. transplantation but not that of lung colony formation. Treatment with corticosteroids or treatment with carrageenan to suppress macrophage activity added toxicity and did not improve the success of xenografting. Immune suppression decreased the natural killer cell activity of normal mice and treatment with antiinterferon to further suppress natural killer cells may also enhance xenograft formation. Administration of cyclosporin A to normal mice allowed the growth of a single xenograft but was not a useful method for immunosuppression. The success of xenografting into immune-deprived mice was superior to that for two strains of nude mice maintained in our laboratory, and i.v. injection of tumor cells did not lead to lung colonies in these nude mice. Immune-deprived mice are a useful alternative to nude mice for the study of xenografts derived from human tumor cell lines and may allow the study of experimental lung metastases.

Animals↗
PubMed1986

Experimental models of bladder cancer: a critical review.

We have reviewed critically the available models of bladder cancer, and have attempted to compare their strengths and weaknesses where appropriate data are available. Further direct comparisons of the applications of each model will be needed in order to rank them, and to identify areas of research where each model will predominate. Furthermore, more information will be needed to validate each model in the context of human disease. With the increasing range and sophistication of the tools of molecular biology, a very important future direction will be the characterisation of animal and human bladder cancer, and in particular the study of the changes from normal to neoplastic urothelium: tumor markers, chromosomal patterns and oncogenes that are associated with specific biological functions, such as invasion, metastasis and ultimate prognosis. The transfection of normal tissues by oncogenes to yield transformed or immortalised lines may be of critical importance in identifying the nature of neoplastic transformation. The use of animal tumors and xenografts, each with the availability of a physiological internal milieu (although different from human metabolic conditions) may yield useful systems for the testing of new therapeutic approaches. However, of the utmost importance is the continuing need to characterise and validate each model, to avoid multiple publications and nomenclatures pertaining to common lines, and to recognise the limitations of the heavily adapted long term cell lines in vivo and in vitro. The major deficiencies of the available lines continue to be found in the method of their application to basic research, rather than being inherent in themselves. Although there are many theoretical and practical applications of these models, it should not be forgotten that the direct study of human bladder cancer, including the appropriate processing of biopsy specimens, will remain integral to understanding the biology of this disease.

Animals↗
PubMed1985

Criteria of tumor response used in clinical trials of chemotherapy.

We have studied 61 published reports of trials of cancer chemotherapy to evaluate the criteria for tumor response that were used and the adequacy of their description in the publication. Our sample comprised recent articles published in three major journals that addressed the influence of chemotherapy on patients with recurrent or metastatic colorectal cancer, non-small cell lung cancer, and head and neck cancer. Incomplete information was sought through a questionnaire mailed to the senior author of each paper, and 48 of them responded. We conclude that: no article contained all of the information required to define precisely criteria for tumor responses; criteria for tumor response are variable; and differences in response criteria contribute to the wide variation in reported rates of tumor response. Meaningful intercomparison of clinical trials will require the establishment of uniform criteria for assessing and reporting the response of tumors to chemotherapy.

Antineoplastic Agents↗
PubMed1984

The radiation response of human bladder cancer assessed in vitro or as xenografts in immune-deprived mice.

We have studied the response to radiation of cells derived from transitional cell carcinoma (TCC) of the human bladder. In vitro radiation survival curves for two established cell lines, RT-4 and MGH-U1, and for a cell line HB-10 derived recently from biopsy of a metastatic lymph node were characterized by values of D0 and n in the range of 1.1-1.5 Gy and 2-7 respectively. The oxygen enhancement ratio of HB-10 cells was 2.8. Xenografts derived from the line HB-10 were irradiated in vivo under both aerobic and hypoxic conditions and cell survival was assessed in agar. Both aerobic and hypoxic survival curves were similar to that obtained for irradiation of hypoxic HB-10 cells in culture. Another tumor line, HB-15, derived from a cystoscopic biopsy of primary TCC, was maintained by transplantation of xenografts. Regrowth curves for HB-15 xenografts after radiation doses of 10 or 20 Gy were parallel to the growth curve for untreated controls but with volume reduced by factors of about 5 and 20 respectively. Irradiation of HB-15 xenografts under hypoxic conditions conveyed minimal protection as compared to irradiation in air. We conclude that cells derived from TCC of the human bladder exhibit parameters of radiation survival similar to those of other mammalian cells, and that xenografts derived from such cells contain a high proportion of hypoxic cells.

Aerobiosis↗
PubMed1984

Influence of measurement error on assessment of response to anticancer chemotherapy: proposal for new criteria of tumor response.

The decision to use a given type of chemotherapy to treat cancer patients is often based on the prior demonstration that a proportion of similar patients has "responded" in a clinical trial. Most responses are recorded as a partial shrinkage of tumor, defined usually as a greater than 50% shrinkage of the sum of cross-sectional areas of index lesions for at least one month. The errors in categorization of response have been estimated by comparing measurements of several physicians on real or simulated malignant lesions. False categorization of partial response based on a comparison of two measurements of the same lesion was 1.3% and 12.6% for large and small simulated nodules, respectively, 13.1% for malignant neck nodes, and 0.8% for metastatic lung nodules. Partial response for hepatic lesions has been defined by a 50% or 30% decrease in liver span below the costal margin; these definitions led to a false categorization of partial response of 8.5% and 18.4%, respectively. Larger errors are evident when using the current definition of disease progression that requires only a 25% increase in area. False categorization of response is increased by comparing any of serial measurements with the initial lesions, as is usually done clinically. Many published trials have used criteria for response that are subject to large errors; an uncritical interpretation of their results may lead to inappropriate treatment of patients. Based on the results, new criteria for evaluating tumor response are proposed.

Analysis of Variance↗
PubMed1983

Toxicity of aziridinylbenzoquinone for aerobic and hypoxic cells of a transplanted mouse mammary tumor and interaction of the drug with radiation and adriamycin.

Aziridinylbenzoquinone (AZQ), an experimental drug with good tissue penetration, was tested against aerobic and hypoxic cells of the 16/C transplantable mouse mammary tumor. The drug was given alone or with local tumor radiation to kill most of the aerobic cells. The end point of response was growth delay. AZQ gave additive effects with tumor irradiation and was equally effective against aerobic and hypoxic cells. AZQ was also given in combination with Adriamycin, since the latter drug is known to have poor penetration in solid tissue. Combined treatment led to greater antitumor effects than were obtained with maximally tolerated doses of either drug alone. Isobologram analysis of the interaction between the drugs suggested a superadditive effect, and the addition of Adriamycin had little effect on myelosuppression induced by AZQ. The combination of AZQ and Adriamycin is worthy of further study.

Animals↗
PubMed1982

Failure of short-course multiple drug chemotherapy to benefit patients with recurrent or metastatic head and neck cancer.

Fifty-seven patients with advanced cancer (52 with squamous cell carcinoma of the head and neck) were treated with short-course, multiple drug chemotherapy using schedules that were similar to those proposed by Price et al. Chemotherapy consisted of vincristine, methotrexate and folinic acid rescue, bleomycin, and FU, with or without Adriamycin and hydroxyurea. Most patients had received radiation therapy. There were only six objective responses (one CR, five PR) and except for one patient who is alive without disease following subsequent radiation the remissions were of short duration. Most patients tolerated treatment well but there was one toxic death, two sudden deaths of unknown cause, and renal impairment, mucositis, myelosuppression, or bleomycin skin toxicity in 14 others. Our results differ from those of Price et al. and do not support a role for this type of chemotherapy in the treatment of recurrent or metastatic head and neck cancer.

Antineoplastic Agents↗
PubMed1982

Combination chemotherapy used prior to radiation therapy for locally advanced squamous cell carcinoma of the head and neck.

Thirty-three patients with locally advanced squamous cell carcinoma of the head and neck were scheduled to receive two courses of chemotherapy prior to radical radiotherapy. Chemotherapy consisted of moderate-dose methotrexate with leucovorin rescue, bleomycin by infusion, and cisplatin. Loss of body weight and the duration of membrane formation at a specified region of the oral cavity during radiation therapy were used as indices of radiation toxicity: there was no excessive loss of body weight or mucosal reaction in patients who received combined treatment compared to patients in a nonrandomized control group who received radiotherapy alone. Twenty patients (60%) had a greater than or equal to 50% decrease of measurable disease prior to starting irradiation, but only eight patients (24%) are alive and disease-free at a median followup of 16 months. Aggressive chemotherapy does not prevent delivery of subsequent full-dose radiotherapy for squamous cell carcinoma of the head and neck, but this study does not suggest that chemotherapy has a great beneficial effect on long-term survival.

Antineoplastic Agents↗
PubMed1982

Xenografts of human bladder cancer in immune-deprived mice.

Human bladder cancer from cystoscopic biopsies and from established cell lines was transplanted into mice that were immune suppressed by thymectomy plus sequential treatment with 1-beta-D-arabinofuranosylcytosine and whole-body irradiation. Each of four established human bladder cancer cell lines generated transplantable tumors in these mice, and some of the mice developed pulmonary metastases. Eight of 33 cystoscopically obtained biopsies of transitional cell carcinoma and one from a metastatic site led to xenografts that grew progressively, and some of these have been transplanted and/or have generated cell lines in vitro. Xenografts grew after a lag period of 0 to 32 weeks and had doubling times of 9 to 30 days. All of those examined histologically were consistent with transitional cell carcinoma, but some of the xenografts became more or less well differentiated in first and subsequent passages. The immune-deprived mouse is an alternative host to the nude mouse for generation of human tumor xenografts and may be a useful model for study of biological properties and therapeutic response of human bladder cancer.

Animals↗