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Biomedical subjects

I F Tannock

Publications and source records attributed to I F Tannock.

At least 127 records · Page 7Linked to original sources
PubMed1986

Growth and characterization of multicellular tumor spheroids of human bladder carcinoma origin.

We have examined the MGH-U1 human bladder carcinoma cell line and 12 primary bladder carcinoma biopsies for their ability to form spheroids in suspension culture and in multiwell dishes. MGH-U1 cells formed tightly packed spheroids with a necrotic center and viable rim whereas three sublines formed loose aggregates only. Spheroids formed from as few as 100 MGH-U1 cells placed into multiwells. MGH-U1 cells derived from spheroids formed new spheroids more rapidly and and consistently than cells derived from monolayer culture. Spheroid diameter increased at a rapid rate of approximately 100 microns/d in multiwell dishes, and necrosis occurred only in spheroids of diameter greater than 1 mm. Spheroids placed in spinner culture at a higher concentration (approximately 1.5 spheroids/ml) grew more slowly and developed necrosis at smaller diameters. The width of the viable rim of spheroids grown in spinner culture was maintained at approximately 190 microns over a wide range of spheroid diameters (400 to 1000 microns). Sequential trypsinization of spheroids, which stripped layers of cells from the spheroids, demonstrated no difference in the plating efficiency of cells derived from varying depths into the spheroid. Only one of the 12 primary bladder biopsy specimens demonstrated an ability to form spheroids. This biopsy, designated HB-10, formed spheroids that grew linearly over 40 d, formed colonies in methylcellulose culture and grew as xenografts in immune-deprived mice. These studies characterize the MGH-U1 spheroids that are useful in vitro models to study the effects of various treatments for solid tumors and demonstrate the limited capacity of cells from primary human bladder biopsies to form spheroids.

Anthraquinones↗
PubMed1986

Influence of reduced concentration of L-glutamine on growth and viability of cells in monolayer, in spheroids, and in experimental tumours.

L-Glutamine is a requirement for many cells in tissue culture, an intermediate in many metabolic pathways, and an alternative substrate to glucose for energy metabolism. These properties suggest that glutamine concentration might be a determinant of cell viability in tumours, especially in regions that are deficient in other metabolites. We have therefore studied the effects of glutamine depletion on single cells in culture, on spheroids and on experimental tumours. Absence of glutamine suppressed the growth rate of two cell lines, but cells cultured for up to 6 h in the absence of glutamine had no decrease in plating efficiency. There was little effect on growth of MGH-U1 (human bladder cancer) spheroids of varying the glutamine concentration in the range of 0.1 to 2 mM and spheroids exposed to these concentrations did not develop central necrosis. Lower concentration of glutamine suppressed the rate of spheroid growth, and spheroids did not grow in the absence of glutamine. Pseudomonas 7A glutaminase reduced the survival of cells in glutamine-free culture and prevented growth of spheroids. Glutaminase was injected into mice bearing experimental tumours to reduce blood levels of glutamine; some animals also received 15 Gy radiation to their tumours to assess the effects of glutamine levels on surviving nutrient-deprived (i.e. hypoxic) cells. Glutaminase had no effect on cell survival in the Lewis lung tumour or in MGH-U1 xenografts, with or without radiation; glutaminase caused dose-dependent growth delay of the KHT tumour, which was additive to that caused by radiation. The present results suggest that (i) short-term changes of glutamine concentration have small effects on cell viability; and (ii) depletion of glutamine levels in blood through the in vivo use of glutaminase is unlikely to produce major therapeutic effects against nutrient-deprived cells in solid tumours.

Animals↗
PubMed1986

Experimental chemotherapy and concepts related to the cell cycle.

Scheduling of chemotherapy is limited by damage to normal tissues, and tolerated schedules are dependent on normal tissue recovery. Most anticancer drugs are more toxic to proliferating cells and the fall and recovery of granulocyte counts after chemotherapy may be explained by the effect of drugs on rapidly proliferating precursor cells in the bone marrow. It is argued that serious toxicity due to myelosuppression most often occurs because of damage to proliferating precursors that may be recognized in bone marrow rather than to stem cells. In contrast, therapy that is aimed at producing cure or long-term remission of tumours must be directed at killing tumour stem cells. The evidence that tumours contain a limited population of cells which can repopulate the tumour after treatment (and are therefore tumour stem cells) is reviewed critically. While there is quite strong evidence for a limited population of target cells, evidence from studies on metastases suggests that the tumour cells which may express this stem cell property may change with time. The stem cell concept has major implications for predictive assays. Although colony-forming assays appear to have a sound biological background for predicting tumour response, technical problems prevent them from being used routinely in patient management. Cells in tumours are known to be heterogeneous and at least three types of heterogeneity may influence tumour response to drug treatment: the development of subclones with differing properties including drug resistance; variation in cellular properties due to differentiation during clonal expansion; and variation in properties due to nutritional status and micro-anatomy. Heterogeneity in drug distribution within solid tumours may occur because of limited drug penetration from blood vessels, and nutrient-deprived cells in solid tumours may be expected to escape the toxicity of some anticancer drugs as well as being resistant to radiation because of hypoxia. This may occur both because nutrient-deprived cells have a low rate of cell proliferation, and also because of poor drug penetration to them. There is a need for improved understanding of the mechanisms that lead to cell death in tumours. If these mechanisms were understood, it might be possible to simulate them by therapeutic manoeuvres. Recent research from our laboratory suggests that the combination of low extracellular pH and hypoxia may be very toxic to cells in nutrient-deprived regions. Drugs which limit the cell's ability to survive in regions of acid pH may provide strategy for therapy of nutrient-deprived cells.

Animals↗
PubMed1986

Lack of evidence for a role of chemotherapy in the routine management of locally advanced head and neck cancer.

Numerous single-arm studies have shown that chemotherapy may produce a high rate of response and rapid shrinkage of tumor when used before radiation and/or surgery in patients with squamous-cell carcinoma of the head and neck. Despite this high rate of tumor response, randomized controlled trials do not indicate any consistent improvement in survival for patients receiving chemotherapy as compared with patients receiving local treatment alone. This population of patients often has poor performance status, and chemotherapy invariable adds some toxicity. Also, studies in animals suggest that some types of chemotherapy given before local radiation or surgery might increase the probability of distant metastases. Apart from pilot studies of feasibility, all future trials of chemotherapy should involve a randomized comparison with a group of patients receiving radiation and/or surgery alone. At present, chemotherapy has no place in the routine management of primary head and neck cancer.

Antineoplastic Agents↗
PubMed1986

Influence of glucose concentration on growth and formation of necrosis in spheroids derived from a human bladder cancer cell line.

Spheroids derived from the human bladder cancer cell line MGH-U1 were initiated in spinner culture and then transferred to multiwell plates which contained medium with varying concentrations of glucose and pyruvate. Growth of individual spheroids was monitored, and at different times after transfer spheroids were sectioned and the diameter of the necrotic center and the thickness of the viable rim were determined. In normal medium containing glucose (1 g/liter; 5.5 mM), spheroid diameter increased linearly with time, growing from approximately 400 micron to approximately 1200 micron in 8 days, and most spheroids did not develop central necrosis. Increase in glucose concentration up to 5 g/liter had no effect on spheroid growth. Lower glucose concentration decreased the rate of spheroid growth, but large effects were observed only at glucose concentration lower than 100 mg/liter. Spheroids developed central necrosis at 2-4 days after transfer to glucose-deficient medium, and the diameter of the necrotic center increased more rapidly than the diameter of the spheroid. There was an approximately linear relationship between thickness of the viable rim in 5-6-day spheroids and glucose concentration in the range of zero (rim thickness, approximately 150 micron) to 500 mg/liter (rim thickness, approximately 400 micron). The presence or absence of pyruvate (110 mg/liter) in the medium had no effect on spheroid growth or formation of necrosis. These results suggest that limited penetration of glucose may be one of the factors that contribute to cell death in solid tumors.

Cell Line↗
PubMed1986

Influence of hypoxia and an acidic environment on the metabolism and viability of cultured cells: potential implications for cell death in tumors.

Hypoxia and an acidic environment are known to occur in regions of solid tumors and might be involved in the causation of necrosis. The viability and energy metabolism of cells in tissue culture were therefore investigated under hypoxic and/or acidic conditions. Acute exposure of Chinese hamster ovary (CHO) cells or human bladder cancer MGH-U1 cells to hypoxia plus low pH (6.5 to 6.0) was cytotoxic in a time- and pH-dependent manner; surviving fraction was reduced to approximately 10(-4) following a 6-h exposure to hypoxia at pH 6.0. There was no effect on viability when aerobic CHO cells were exposed for 6 h at pH 6.0, or when either cell line was rendered hypoxic for 6 h at pH 7.0; MGH-U1 cells showed slight sensitivity to acidic pH in air. Decrease in viability of CHO cells incubated under acid conditions was observed over the range of oxygen concentrations from 0.2 to 0.05%, similar to the range which causes change in cellular sensitivity to radiation. Glucose consumption and lactate production by both cell lines were inhibited at low pH under both aerobic and hypoxic conditions. Cellular adenosine triphosphate (ATP) levels and the energy charge [(ATP + 1/2 adenosine diphosphate)/(adenosine monophosphate + adenosine diphosphate + ATP)] of CHO cells were reduced by about 85 and 25%, respectively, after a 6-h exposure to hypoxia at pH 6.0 but were not influenced by hypoxia or acid pH alone. Inhibition of glycolysis by incubation of CHO cells under hypoxic conditions in the absence of glucose (at pH 7.0) led to a larger fall in cellular ATP and energy charge, but cell survival fell to only approximately 10(-2) at 6 h. These results demonstrate that hypoxia and an acid environment interact to cause marked toxicity. A decrease in energy charge of the cells may contribute to loss of viability, but additional mechanisms appear to be involved.

Adenosine Triphosphate↗
PubMed1985

Is there evidence that chemotherapy is of benefit to patients with carcinoma of the prostate?

Most patients with metastatic carcinoma of the prostate have osteoblastic bone metastases and nonmeasurable pelvic disease. These features cause patients to be at high risk for myelosuppression after cytotoxic chemotherapy and make it difficult to evaluate response to treatment. A critical review of larger trials that have sought to assess the role of chemotherapy in treatment of carcinoma of the prostate leads to the following conclusions: (1) Although the aim of treatment is palliation, most trials have tried to evaluate tumor response rather than the more appropriate endpoints of quality and quantity of survival for all treated patients. (2) Criteria that have been used for tumor response are variable and contain large inherent errors; most patients who are labeled as "responders" are described as being "objectively stable," but this category may be a manifestation of slowly progressive disease rather than a response to treatment. (3) There is no evidence that chemotherapy causes a meaningful prolongation of survival. (4) Chemotherapy adds considerable toxicity, and reported trials have not adequately assessed its overall impact on quality of life. Because of these factors there is little evidence that chemotherapy provides palliation for patients with prostatic carcinoma, and it should not be regarded as part of standard management. Selected patients who are symptomatic and no longer responding to hormones may be considered for trials of chemotherapy. Future trials should randomize patients to chemotherapy or supportive care, with assessment of quality and quantity of survival for all randomized patients by an observer who is unaware of the treatment.

Antineoplastic Agents↗
PubMed1984

The effect of the drug lonidamine on Chinese hamster ovary cells in vitro and on experimental tumors.

Hypoxic cells in solid tumors are known to be resistant to radiation, and may also be resistant to some anti-cancer drugs. Biochemical properties of hypoxic cells, such as their dependence on anaerobic glycolysis leading to production of lactate and low pH might have potential for inhibition by drugs with selective activity against hypoxic cells. Such drugs might improve the Therapeutic Index when used with radiation or some conventional anti-cancer drugs. Preliminary studies have shown that the combination of hypoxia and low pH (pH 6.5-6.0) was cytotoxic to Chinese Hamster Ovary (CHO) cells incubated in vitro for up to 6 hours, although neither factor alone reduced plating efficiency. Lonidamine, an inhibitor of mitochondrially-bound hexokinase and lactate transport, was cytotoxic to CHO cells at low pH, but had no effect at physiological pH under aerobic or hypoxic conditions. Lonidamine has also been tested for in vivo effects against three murine tumors: the KHT fibrosarcoma, 16/C mammary carcinoma and the Lewis Lung Tumor. The drug was tested either alone, or with radiation or Adriamycin to kill aerobic cells, and/or with glucose and insulin to lower intra-tumor pH. No major therapeutic effects have been demonstrated.

Animals↗
PubMed1984

Chemotherapy for head and neck cancer.

This overview of the role of chemotherapy in head and neck cancer is based on clinical trials conducted at The Princess Margaret Hospital and on a critical review of the literature. For recurrent or metastatic squamous cell carcinoma, no drug or combination has been found superior to methotrexate, which in large series gives transient responses in about 25% of patients. Reports of higher rates of response have not correlated with increased survival, and response rates from many series have been inflated by the use of poor and variable criteria of response or by inappropriate exclusion of patients. Chemotherapy may lead to high rates of response when used initially as part of combined modality treatment with radiation and/or surgery, but longterm benefit has not yet been demonstrated. Chemotherapy should not be considered part of standard management for recurrent or metastatic head and neck cancer, and should be used as part of primary treatment for loco-regional disease only in the context of large, well designed clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Comparison of growth of human bladder cancer in tissue culture or as xenografts with clinical and pathological characteristics.

Seventy-four biopsies of human bladder carcinoma were assessed by implantation as xenografts in immune-deprived mice and/or by culture of cell suspensions in agar or methylcellulose. The quality of the cell suspensions was assessed immediately after plating in vitro. The results were compared with the pathological stage and grade of the biopsies and with the clinical course of the disease in patients from whom the biopsies were obtained. We found that (a) progressively growing xenografts were generated from 20 of 53 biopsies (38%). These xenografts grew with mean volume doubling times in the range of 1 to 3 weeks; all of them examined histologically were consistent with transitional cell carcinoma. (b) Colony formation occurred from 21 of 49 cell suspensions (43%), and plating efficiency was in the range of 0.0004 to 1.7%. The majority of cell suspensions were found to have residual small clusters of cells. Colony formation sometimes originated from these clusters, an effect that would be expected to introduce artifacts when the in vivo cloning assay is used for chemosensitivity testing. (c) There was no evident correlation between expression of clonal growth in vitro and success of xenografting, and no correlation between the results of either of these experimental procedures with stage, grade, or clinical course of the disease. Further improvements in tissue culture and xenograft technology will be required before these methods can be used as a guide to patient management.

Animals↗
PubMed1983

Chemotherapy for metastatic transitional carcinoma of the urinary tract. A prospective trial of methotrexate, adriamycin, and cyclophosphamide (MAC) with cis-platinum for failure.

Fifty-two patients with metastatic transitional cell carcinoma (TCC) of the urinary tract were treated with methotrexate, Adriamycin and cyclophosphamide (MAC). Objective responses lasting at least three months were seen in 15 (two CR, 13 PR) of 38 patients with measurable disease (response rate = 39%, with 95% confidence limits 24-57%). Median duration of response was six months (range, 3-12 months). In addition, there was clinical or other evidence of response for greater than or equal to 3 months in four of 14 patients with evaluable but nonmeasurable lesions. Sixteen patients who failed or relapsed after MAC chemotherapy received cis-platinum and none responded. MAC chemotherapy can provide significant palliation to some patients with TCC and is usually better tolerated than cis-platinum.

Adult↗
PubMed1983

Biology and tumor growth.

Why do malignant tumors initially grow rapidly, then more slowly? What accounts for the different rats of growth among different tumors? Can the answers to these and related questions enable us to improve the results of cancer therapy? With advanced technology, we have come a long way in penetrating the mechanisms of tumor cell kinetics, but to date clinical strategies have not kept pace.

Animals↗
PubMed1983

Failure of 2-deoxy-D-glucose and 5-thio-D-glucose to kill hypoxic cells of two murine tumors.

We have administered the glycolysis inhibitors 2-deoxy-D-glucose and 5-thio-D-glucose to C3H/HeJ mice bearing KHT or 16/C transplantable tumors to seek evidence for hypoxic cell toxicity in vivo. The drugs were given (a) with or without insulin, (b) as large single doses or as multiple hourly injections, and (c) alone or immediately after the tumors had received radiation to kill most of the aerobic cell population. Tumor response was assessed by growth delay or by lung colony assay. Limiting toxicity of 2-deoxy-D-glucose and 5-thio-D-glucose was neurological, leading to seizures and/or death, and this toxicity was increased by insulin. The drugs had at most minimal effects on the growth of either untreated or irradiated tumors at maximal tolerated doses. Despite the known selective toxicity of these glucose analogues for hypoxic cells in tissue culture, we have found them to be ineffective in killing hypoxic cells of two murine tumors.

Adenocarcinoma↗
PubMed1983

Methotrexate and mitomycin for patients with metastatic transitional cell carcinoma of the urinary tract.

Sixteen patients who had received no prior chemotherapy were treated with methotrexate and mitomycin for metastatic transitional cell carcinoma of the urinary tract. Five patients achieved partial response, with a median duration of 3 months (range, 3-8), but the trial has been abandoned because of severe toxic effects in six of the 16 patients. This combination appears to be more toxic and no more effective than methotrexate alone.

Antineoplastic Agents↗