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Biomedical subjects

H Thames

Publications and source records attributed to H Thames.

14 recordsLinked to original sources
PubMed1995

Does tumor control decrease by prolonging overall treatment time or interrupting treatment in laryngeal cancer?

PURPOSE: To evaluate treatment results of radiotherapy in laryngeal cancer and to retrospectively investigate the influence of treatment interruptions on local control rates. A multivariate analysis was performed to investigate the role of overall treatment time on local control rates. MATERIAL AND METHODS: From 1962 to end 1986, 864 patients with cancer of the larynx were treated with primary radiotherapy, with a variation of doses and treatment times. In 352 patients a systematic interruption of 2 weeks was done after 50 Gy (split-course). Local control rates were calculated by the actuarial method. A multivariate analysis was subsequently performed in order to identify independent variables influencing local control rates. RESULTS: The univariate analysis showed that in patients treated with a split-course schedule, local control rates were significantly lower in glottic cancer (p < 0.001), with differences of 7% in T1 (p = 0.05) and 11% in T2 (p = 0.11). In node-negative supraglottic cancer a difference of 10% (p = 0.16) was observed. The multivariate analysis showed the following factors to significantly influence local control: site, total dose, total treatment time, T and N stage. Split-course treatment was not an independently significant factor, probably caused by time being a stronger factor. In subgroup analysis, the effect of total treatment time remained statistically significant in T2 glottic cancer. CONCLUSION: A significant negative influence of treatment interruption was seen in glottic cancer, and a trend toward significance in node-negative supraglottic cancer in univariate analysis. A multivariate analysis showed a negative influence of prolonging treatment time in the total patient group. The effect remained significant in T2 glottic cancer in subsequent subgroup analysis, possibly due to the fact that there is little variation in tumour volume in this group. In larger tumours, where there is substantial variation in tumour volume and a higher probability of heterogeneity in radiosensitivity, the effect of dose-time variations could be more difficult to discern.

Female↗
PubMed1994

Dynamics of tumor cell clonogen repopulation in a murine sarcoma treated with cyclophosphamide.

Experiments were performed to establish the extent and kinetics of tumor cell repopulation in a murine sarcoma, designated SA-NH, treated with cyclophosphamide (CY). Mice bearing 8-mm leg tumors were treated with 200 mg/kg CY which caused a transient tumor regression. Changes in the absolute clonogen content of tumors was determined by the change in TCD50 values (50% tumor control) obtained under hypoxic conditions of local tumor irradiation at different times after CY treatment until tumors regrew to the pretreatment size. For comparison, hypoxic TCD50 values were determined during the growth of tumors not treated with CY. CY greatly depleted tumors of clonogenic cells as manifested by the reduction in the control TCD50 value of 64.5 Gy to 32.8 Gy 1 day after CY treatment. The reduced TCD50 value remained unchanged for 2 weeks after treatment with CY, at which time the TCD50 began to rapidly increase, continuing until the end of the observation period of 21 days when tumors reached the pretreatment size. In contrast, there was a constant but slower increase in TCD50 values during the growth of tumors not treated with CY. The daily increase in TCD50 was more than twice as high in CY-treated than in CY-untreated tumors: 4.5 Gy/day versus 2.1 Gy/day. This implies that the rate of clonogen production in CY-treated tumors was twice as high as that of unperturbed tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The clonogenic growth of advanced breast tumour lesions adds no value to that of established clinical prognosticators for survival.

We measured the clonogenic growth of 110 breast cancer samples obtained from 107 patients with advanced disease. We determined clonogenicity under conventional conditions and under conditions supplemented with growth factors and hormones that target breast tissue. After a median follow-up period of 6 years we analyzed our data to determine if and to what degree clonogenic growth of metastatic breast tumours was related to the survival of patients. We found that tumour clonogenicity and patient survival correlated weakly, particularly if compared to the strong correlations of patient survival with either performance status or tumour bulk. Furthermore, an association between tumour clonogenicity and patient survival was visible only for clonogenicity that was determined under hormone-supplemented conditions, and only for tumour lesions that formed 50 or more colonies per 500,000 cells cultured. Thus, we conclude that clonogenic growth of breast tumour samples incompletely reflects the tumour features that determine the course of advanced disease.

Breast Neoplasms↗
PubMed1989

Predictors of hormone response for patients with ER-unknown breast tumours.

Characteristics of cells that are associated with the hormonal dependence of tumours are described, and it is shown that clonogenicity and hormone-induced proliferative response of breast tumours are as good markers of hormonal dependence as is oestrogen receptor. Thus tumours that formed less than 150 colonies per 500,000 cells seeded and that increased their proliferative activity 1.8-fold or more in response to hormones were the tumours that were likely to respond to endocrine treatments, whereas all other tumours were likely to be refractory to endocrine treatments. These two criteria (clonogenicity and proliferative response to growth hormones) correctly identified the response to subsequent endocrine treatments in 15 out of 17 patients with oestrogen receptor-unknown tumours. It is proposed that they may constitute a substitute for the oestrogen receptor status in patients with non-biopsiable tumours, and an additional discriminant where the oestrogen receptor assay is available.

Breast Neoplasms↗
PubMed1988

Chemotherapy and hormonal therapy in combination.

The advantage of adding hormones to chemotherapy for the treatment of patients with breast carcinoma is uncertain, and benefits and disadvantages have been reported. An analysis of published randomized clinical trials reveals that the growth function (differentiation-inducing function v mitogenic function) of the hormone used may determine the ultimate benefit of combined modality treatments.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Role of culture conditions and exposure duration in determining sensitivity of human bone marrow progenitor cells to methotrexate.

The effect of drug concentration, exposure duration, and culture conditions on the cytotoxic activity of methotrexate (MTX) on normal granulocyte-macrophage colony-forming units in culture (GM-CFUC) was studied using a bilayer soft agar system with nucleoside-free medium. The degree of inhibition of colony formation depended on the type of serum supplementation. A 1 h or 2 h pulse treatment with 2 X 10(-4) M (100 micrograms/ml) MTX failed to kill GM-CFUC, when the cells were subsequently plated in a system containing 15% undialyzed fetal bovine serum (FBS). For continuous exposure the observed LD50 of MTX in the agar system was higher than 10(-4) M for 15% undialyzed FBS, 10(-5) M for 15% dialyzed FBS plus 0.25% undialyzed FBS, 10(-6) M for 15% dialyzed FBS, and 10(-8) M for 15% undialyzed horse serum. The difference for dialyzed FBS versus horse serum can be explained by differences in nucleoside concentrations. The difference for dialyzed FBS versus horse serum may be secondary to an enhancer of MTX in horse serum. For studying MTX sensitivity of human tumor cells in vitro, we suggest testing conditions that lie within the dose survival curve of GM-CFUC.

Culture Media↗
PubMed1986

Chemosensitivities of human clonogenic breast tumor cells.

We developed an in vitro system for the testing of the inherent chemosensitivity of clonogenic tumor cells, and we applied the system to the evaluation of 104 human breast tumors. We observed the following: clonogenic breast tumor cells were more sensitive to 4-hydroperoxy-cyclophosphamide (a metabolite of cyclophosphamide with in vitro activity) than to 5-fluorouracil and to doxorubicin (the other two agents used in the frontline treatment of breast carcinoma). The sensitivity of these clonogenic breast tumor cells for mitoxantrone, bisantrene, 4'-epi-doxorubicin, and VP-16 was similar to that for doxorubicin and 5-fluorouracil, but it was less for cis-platinum. In vivo exposure to a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) did not change the sensitivity of cells towards 5-fluorouracil and doxorubicin, but lessened the sensitivity of some cells towards 4-hydroperoxycyclophosphamide. Furthermore, in vivo exposure to doxorubicin did not influence the sensitivity of cells towards the anthraquinone derivatives, 4'-epi-doxorubicin, mitoxantrone, and bisantrene. A comparison of the in vitro and in vivo chemosensitivity revealed that the assayed cell populations were biologically relevant: the concordance of sensitivity on 41 tumors was 68%, or 95%, if the in vitro sensitivity score was adjusted to the tumor bulk. We conclude that our system provides a valid tool to determine the inherent chemosensitivity pattern of the individual tumor types, and to compare the tumor cytotoxic potential of drugs.

Antineoplastic Agents↗
PubMed1985

Survival of human bone marrow cells after in vitro treatment with 12 anticancer drugs and implications for tumor drug sensitivity assays.

We investigated the responsiveness of human normal granulocyte-macrophage colony-forming units in culture (GM-CFUC) continuously exposed in vitro to 1 of 12 anticancer drugs. All drugs except bleomycin showed a simple negative exponential dose-survival curve. The in vitro toxicity of drugs in GM-CFUC did not always correlate with the relative myelosuppressive potency observed in vivo. In addition, tumor specimens from 38 patients mainly with ovarian cancer were cultured in a human tumor colony-forming assay and continuously exposed to drugs at low, intermediate, and high concentrations capable of killing 40%, 78%, and 99% of GM-CFUC, respectively. The most active drugs were cis-platinum, velban, 5-fluorouracil, and 5-fluoro-ara-AMP. Dose-survival curves of bone marrow progenitor cells may serve as an in vitro reference system for selecting appropriate drug concentrations of myelosuppressive drugs in drug-sensitivity assays of human tumors.

Antineoplastic Agents↗
PubMed1984

Responses of human bone marrow progenitor cells to fluoro-ara-AMP, homoharringtonine, and elliptinium.

The cytotoxicity of the investigational anticancer drugs fluoro-ara-AMP, homoharringtonine, and elliptinium on normal human granulocyte-macrophage colony-forming units in culture (GM-CFU) was investigated using a bilayer soft agar system. For each drug, the dose-dependent survival curve on a semilogarithmic plot formed a straight line. The D0 were: 0.51 microgram/ml (fluoro-ara-AMP), 0.004 microgram/ml (homoharringtonine) and 0.026 microgram/ml (elliptinium). The in vitro toxicity of drugs on bone marrow progenitor cells did not correlate with the relative myelosuppressive potency observed in vivo.

Alkaloids↗
PubMed1984

The true predictive value of the human tumor stem cell assay: does a workable assay select for treatment responders?

In practice, the human tumor clonogenic assay is workable for less than half of the patient population to which it is applied, since the remainder of the specimens fail to produce sufficient numbers of colonies. Thereby a bias may be introduced which could result in a false predictive value positive of the test. It is therefore necessary to compare the responses to treatment of patients whose tumors could be assayed in vitro to those whose tumors failed to grow adequately, to assure that the prevalence of treatment responders has not changed within the group of patients for which the assay worked. From an analysis of the treatment response of 70 patients with stage III and IV ovarian carcinomas and 70 patients with stage IV breast cancer, no selection bias did occur and no preferential in vitro growth of tumor samples from patients with treatment response was found.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Normalization of in vitro sensitivity testing of human tumor clonogenic cells.

The use of normal bone marrow (granulocyte-macrophage colony-forming units) as a point of reference to normalize the in vitro activities of anticancer agents has been investigated. The cytotoxic effects of four substituted anthraquinone derivatives, and of vinblastine on myeloid progenitors of different donors were reproducible up to a cell kill of approximately 60%. Equitoxic in vitro concentrations for normal bone marrows did not correlate with in vivo pharmacokinetic concentrations of these drugs. Breast tumor progenitor cells of 46 specimens were more sensitive than were bone marrow progenitors to the anthraquinone derivatives in 26 to 39% of instances, ratios which are similar to the clinically observed response rates of patients with breast carcinoma to these agents. Tumors were either sensitive or resistant to all four drugs in 68% (10 tumors were more sensitive, and 21 tumors were less sensitive than normal bone marrow); but in 32% of instances there were differences in tumor sensitivity for the four drugs, and the assay could select one to three drugs for which the tumor sensitivity was greater than that of bone marrow. Correlations of in vitro sensitivity and of clinical response to single agent treatments were determined in 21 patients, and the concordance was 71%. The value of the assay in predicting clinical response ranked best for sensitivity determinations within the normalized dose ranges, when testing within three different dose ranges was compared in a group of six patients. The concordance was higher in the small (1 or 2 metastatic sites) than in the large (greater than or equal to 3 metastatic sites) tumors (85 versus 50%), indicating a confounding influence of tumor load on the ability of the assay to predict efficacy of treatment. A rule of thumb is proposed for altering the in vitro sensitivity test results for large tumors that improves the overall concordance to 90%.

Antineoplastic Agents↗