Biomedical subjects

J C Martin

Publications and source records attributed to J C Martin.

At least 37 records · Page 2Linked to original sources

PubMed2001

[Specific bronchial provocation test with solid aerosols. Quantification of results].

OBJECTIVES: To determine 1) the level of specific bronchial reactivity by challenge with flour and 2) the criteria of positivity using a new method for the expression of the results. METHOD: Thirty-eight asthmatic subjects, occupationally exposed to wheat flour, performed a challenge with lactose then with flour. The instantaneous measurement of the concentration and of the inspiratory airflow were used to calculate the inhaled dose and to establish the dose-response relationships. The results were given 1) by the dose of flour provoking a 20% fall in FEV1 (PDf20), 2) by the comparison of the variation of the FEV1 during the challenge with flour to the distribution of the values observed during the challenge with lactose (inferior limit of the confidence interval at 99.7%). RESULTS: The variations of the FEV1 were not significantly related to the inhaled dose of lactose. The specific bronchial reactivity to flour was a continuous data and three groups were distinguished: 1) subjects (n = 15) with high bronchial reactivity had a fall of FEV1 of more than 20% 2) subjects (n = 13) without significant variation of the FEV1 for doses higher than 1,400 micrograms by comparison to the distribution of the values of the lactose test 3) subjects (n = 10) with a significant fall of FEV1 by comparison to the distribution of the values of the lactose test but lower than 20%. For this group with moderate reactivity, the flow of the inhaled dose may be determinant for the bronchial response. CONCLUSIONS: PDf 20 measures the specific bronchial reactivity. However, if the fall in FEV1 is lower than 20%, the specific challenge with flour may be compared to the challenge with lactose to detect the subjects with moderate reactivity. Our results confirmed the role of the inhaled dose and suggested the role of the dose rate in the outset of bronchial obstruction among asthmatic subjects.

Administration, Inhalation↗

PubMed2000

Occupational risk factors for lung cancer in the French electricity and gas industry: a case-control survey nested in a cohort of active employees.

The main aim of this study was the analysis of occupational lung cancer risk factors in the French national electricity and gas company (Electricité de France-Gaz de France (EDF-GDF)). A case-control survey nested in a cohort of male employees was undertaken. The study population consisted of all male staff who were active at EDF-GDF between January 1, 1978, and December 31, 1989. During this period, 310 cases of lung cancer were identified in the cancer register set up by the medical department of the company. For each case, four age-matched controls who were free of cancer at the time of occurrence of the case's lung cancer were randomly selected. Occupational exposures to 21 chemical agents were assessed for each subject using a job exposure matrix. The associations between lung cancer and the different agents were estimated using conditional logistic regression analysis. After adjustment for various occupational confounding factors, the analysis showed increased lung cancer risks linked to exposure to crystalline silica (highest exposure class: odds ratio = 2.27; 95% confidence interval: 1.10, 4.68) and creosotes (highest exposure level: odds ratio = 2.14; 95% confidence interval: 1.06, 4.31), with significant dose-response relationships for both exposures.

Adult↗

PubMed2000

Effects of conjugated linoleic acid isomers on lipid-metabolizing enzymes in male rats.

Male weanling Wistar rats (n = 15), weighing 200-220 g, were allocated for 6 wk to diets containing 1% (by weight) of conjugated linoleic acid (CLA), either as the 9c,11 t-isomer, the 10t,12c-isomer, or as a mixture containing 45% of each of these isomers. The five rats of the control group received 1% of oleic acid instead. Selected enzyme activities were determined in different tissues after cellular subfractionation. None of the CLA-diet induced a hepatic peroxisome-proliferation response, as evidenced by a lack of change in the activity of some characteristic enzymes [i.e., acyl-CoA oxidase, CYP4A1, but also carnitine palmitoyltransferase-I (CPT-I)] or enzyme affected by peroxisome-proliferators (glutathione S-transferase). In addition to the liver, the activity of the rate-limiting beta-oxidation enzyme in mitochondria, CPT-I, did not change either in skeletal muscle or in heart. Conversely, its activity increased more than 30% in the control value in epididymal adipose tissue of the animals fed the CLA-diets containing the 10t,12c-isomer. Conversely, the activity of phosphatidate phosphohydrolase, a rate-limiting enzyme in glycerolipid neosynthesis, remained unchanged in adipose tissue. Kinetic studies conducted on hepatic CPT-I and peroxisomal acyl-CoA oxidase with CoA derivatives predicted a different channeling of CLA isomers through the mitochondrial or the peroxisomal oxidation pathways. In conclusion, the 10t,12c-CLA isomer seems to be more efficiently utilized by the cells than its 9c,11t homolog, though the Wistar rat species appeared to be poorly responsive to CLA diets for the effects measured.

Acyl-CoA Oxidase↗

PubMed2000

A governing relationship for repetitive muscular contraction.

During repetitive contractions, muscular work has been shown to exhibit complex relationships with muscle strain length, cycle frequency, and muscle shortening velocity. Those complex relationships make it difficult to predict muscular performance for any specific set of movement parameters. We hypothesized that the relationship of impulse with cyclic velocity (the product of shortening velocity and cycle frequency) would be independent of strain length and that impulse-cyclic velocity relationships for maximal cycling would be similar to those of in situ muscle performing repetitive contraction. Impulse and power were measured during maximal cycle ergometry with five cycle-crank lengths (120-220mm). Kinematic data were recorded to determine the relationship of pedal speed with joint angular velocity. Previously reported in situ data for rat plantaris were used to calculate values for impulse and cyclic velocity. Kinematic data indicated that pedal speed was highly correlated with joint angular velocity at the hip, knee, and ankle and was, therefore, considered a valid indicator of muscle shortening velocity. Cycling impulse-cyclic velocity relationships for each crank length were closely approximated by a rectangular hyperbola. Data for all crank lengths were also closely approximated by a single hyperbola, however, impulse produced on the 120mm cranks differed significantly from that on all other cranks. In situ impulse-cyclic velocity relationships exhibited similar characteristics to those of cycling. The convergence of the impulse-cyclic velocity relationships from most crank and strain lengths suggests that impulse-cyclic velocity represents a governing relationship for repetitive muscular contraction and thus a single equation can predict muscle performance for a wide range of functional activities. The similarity of characteristics exhibited by cycling and in situ muscle suggests that cycling can serve as a window though which to observe basic muscle function and that investigators can examine similar questions with in vivo and in situ models.

Adult↗

PubMed2000

Time course of learning to produce maximum cycling power.

The purpose of this investigation was to determine the time course and magnitude of learning effects associated with repeated maximum cycling power tests and to determine if cycle-trained men exhibit different learning effects than active men who are not cycle-trained. Cycle-trained (N = 13) and active men (N = 35) performed short maximal cycling bouts 4 times per day for 4 consecutive days. Inertial load cycle ergometry was used to measure maximum power and pedaling rate at maximum power. Maximum power of the cycle-trained men did not differ across days or bouts. Maximum power of the active men increased 7 % within the first day and 7 % from the mean of day one to day three. Pedaling rate at maximum power did not differ across days or bouts in either the cycle-trained or active men. These results demonstrate that valid and reliable results for maximum cycling power can be obtained from cycle-trained men in a single day, whereas active men require at least 2 days of practice in order to produce valid and reliable values.

Adult↗

PubMed2000

Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health?

BACKGROUND: The role of nutritional influences on bone health remains largely undefined because most studies have focused attention on calcium intake. OBJECTIVE: We reported previously that intakes of nutrients found in abundance in fruit and vegetables are positively associated with bone health. We examined this finding further by considering axial and peripheral bone mass and markers of bone metabolism. DESIGN: This was a cross-sectional study of 62 healthy women aged 45-55 y. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at the lumbar spine and femoral neck and by peripheral quantitative computed tomography at the ultradistal radial total, trabecular, and cortical sites. Bone resorption was calculated by measuring urinary excretion of pyridinoline and deoxypyridinoline and bone formation by measuring serum osteocalcin. Nutrient intakes were assessed by using a validated food-frequency questionnaire; other lifestyle factors were assessed by additional questions. RESULTS: After present energy intake was controlled for, higher intakes of magnesium, potassium, and alcohol were associated with higher total bone mass by Pearson correlation (P < 0.05 to P < 0.005). Femoral neck BMD was higher in women who had consumed high amounts of fruit in their childhood than in women who had consumed medium or low amounts (P < 0.01). In a regression analysis with age, weight, height, menstrual status, and dietary intake entered into the model, magnesium intake accounted for 12.3% of the variation in pyridinoline excretion and 12% of the variation in deoxypyridinoline excretion. Alcohol and potassium intakes accounted for 18.1% of the variation in total forearm bone mass. CONCLUSION: The BMD results confirm our previous work (but at peripheral bone mass sites), and our findings associating bone resorption with dietary factors provide further evidence of a positive link between fruit and vegetable consumption and bone health.

Absorptiometry, Photon↗

PubMed2000

Maximal power across the lifespan.

BACKGROUND: Previous investigators have reported that maximal power increases during growth and decreases with aging. These age-related differences have been reported to persist even when power is scaled to body mass or muscle size. We hypothesized that age-related differences in maximal power were primarily related to differences in muscle size and fiber-type distribution rather than to age per se. METHODS: Maximum cycling power (Pmax) and optimal pedaling rate (Vopt, a surrogate measure for muscle fiber type) were determined for 195 boys and men, 8-70 years of age, by using inertial load cycle ergometry. Anthropometric dimensions were used to estimate lean thigh volume (LTVest) of all subjects, and magnetic resonance imagery was used to determine thigh and hip muscle volume (MRIvol) for 24 subjects. RESULTS: Pmax was highly related to the product of LTVest and Vopt (LTVest X Vopt; r2 = .83). Multiple regression revealed that Pmax was significantly related to both LTVest x Vopt and age (R2 = .84). Power scaled by LTVest X Vopt was stable during growth and exhibited a small but significant decrease with aging. MRIvol was highly correlated with LTVest, and the ratio of LTVest to MRIvol was independent of age. CONCLUSIONS: These results suggest that muscle volume and optimal pedaling rate are the main determinants of maximal power across the lifespan and that the contractile properties of muscle are developed early in childhood and remain nearly intact late into the lifespan.

Adolescent↗

PubMed2000

Lymphatic delivery and in vitro pancreatic lipase hydrolysis of glycerol esters of conjugated linoleic acids in rats.

We examined the intestinal delivery of conjugated linoleic acids (CLA) given in their triacylglycerol form in the mesenteric lymph of rats. Emulsions containing a mixture of the trilinolein/triester of CLA (9:1) and a tri-[1-(14)C]-linoleyl-sn-glycerol tracer were administered by force-feeding. Lymph was collected over two time periods (0-6 and 6-24 h), and the apparent recovery of CLA was determined relative to that of [1-(14)C]-18:2(n-6). A mixture of CLA-triester/trilinolein (1:9), trilinolein or CLA-triester was separately subjected to pancreatic lipase hydrolysis in vitro to determine whether the lymphatic recovery of CLA was correlated with the initial step of digestion. Lymphatic recovery of CLA was similar to that of 18:2(n-6) (95.6+/-9.0% of the linoleic acid recovery), and isomer repartition was similar in lymph and in the oil fed, indicating that all the CLA isomers were equally absorbed by the enterocytes. Unexpectedly, the in vitro release of CLA into the absorbable forms (free fatty acids and 2-monoacyl-sn-glycerol) was consistently lower than that of 18:2(n-6). Moreover, the 9c, 11t-isomer of CLA was also released faster into the absorbable forms than its 10t,12c homolog (P = 0.05). We cannot ascribe a distinct cellular accumulation or a difference in the biological effects of different CLA isomers on the ground of a selective intestinal absorbability. Also, the physiological conditions prevailing in vivo in the digestive tract are likely to overcome the relative resistance of CLA ester bonds to pancreatic lipase hydrolysis and allow a lymphatic recovery of CLA similar to that of linoleic acid.

Analysis of Variance↗

PubMed2000

Cyclic fatty acid monomers from heated oil modify the activities of lipid synthesizing and oxidizing enzymes in rat liver.

Cyclic fatty acid monomers purified from a heated linseed oil were given for 2 wk to adult rats as triacylglycerol at two dose levels, i.e., 0.1 and 1 g/100 g diet, to determine their effect on some aspects of lipid metabolism. Indirect evidence of a peroxisome proliferator-like effect was observed, as determined by an elevation of some characteristic enzyme activities, such as peroxisomal acyl-CoA oxidase, and the microsomal omega- but also (omega-1)-laurate hydroxylase (CYP4A1 and CYP2E1, respectively). The dietary cyclic fatty acids induced a coordinated regulation between the activities of the lipogenic enzymes studied (Delta9-desaturase, phosphatidate phosphohydrolase) and peroxisomal oxidation, but not with mitochondrial beta-oxidation. The dose-dependent decrease of Delta9-desaturase activity (P < 0.05) with cyclic fatty acid monomer intake was accompanied by a similar decrease of the monounsaturated fatty acid level in liver. The increase in the gamma-linolenic acid level also suggested an increase in Delta6-desaturase activity with cyclic fatty acid intake (P < 0.05). In addition, our results strongly suggested that the altered liver levels of eicosapentaenoic and arachidonic acids were due to the peroxisomal retroconversion process in rats fed cyclic acids. Finally, an effect of these cyclic compounds on the carbohydrate metabolism cannot be disregarded because they decreased liver glycogen concentration. We conclude that cyclic fatty acid monomers affect different aspects of lipid metabolism, including a phenotypic peroxisome proliferator response. This provides the ground for further studies investigating the biochemical pathways that underlie the nutritional effect of such molecules.

Acyl-CoA Oxidase↗

PubMed2000

Phylogenetic relationships of butyrate-producing bacteria from the human gut.

Butyrate is a preferred energy source for colonic epithelial cells and is thought to play an important role in maintaining colonic health in humans. In order to investigate the diversity and stability of butyrate-producing organisms of the colonic flora, anaerobic butyrate-producing bacteria were isolated from freshly voided human fecal samples from three healthy individuals: an infant, an adult omnivore, and an adult vegetarian. A second isolation was performed on the same three individuals 1 year later. Of a total of 313 bacterial isolates, 74 produced more than 2 mM butyrate in vitro. Butyrate-producing isolates were grouped by 16S ribosomal DNA (rDNA) PCR-restriction fragment length polymorphism analysis. The results indicate very little overlap between the predominant ribotypes of the three subjects; furthermore, the flora of each individual changed significantly between the two isolations. Complete sequences of 16S rDNAs were determined for 24 representative strains and subjected to phylogenetic analysis. Eighty percent of the butyrate-producing isolates fell within the XIVa cluster of gram-positive bacteria as defined by M. D. Collins et al. (Int. J. Syst. Bacteriol. 44:812-826, 1994) and A. Willems et al. (Int. J. Syst. Bacteriol. 46:195-199, 1996), with the most abundant group (10 of 24 or 42%) clustering with Eubacterium rectale, Eubacterium ramulus, and Roseburia cecicola. Fifty percent of the butyrate-producing isolates were net acetate consumers during growth, suggesting that they employ the butyryl coenzyme A-acetyl coenzyme A transferase pathway for butyrate production. In contrast, only 1% of the 239 non-butyrate-producing isolates consumed acetate.

Adult↗

PubMed2000

Water and carbohydrate ingestion during prolonged exercise increase maximal neuromuscular power.

This study investigated the individual and combined effects of water and carbohydrate ingestion during prolonged cycling on maximal neuromuscular power (P(max)), thermoregulation, cardiovascular function, and metabolism. Eight endurance-trained cyclists exercised for 122 min at 62% maximal oxygen uptake in a 35 degrees C environment (50% relative humidity, 2 m/s fan speed). P(max) was measured in triplicate during 6-min periods beginning at 26, 56, 86, and 116 min. On four different occasions, immediately before and during exercise, subjects ingested 1) 3.28 +/- 0.21 liters of water with no carbohydrate (W); 2) 3.39 +/- 0.23 liters of a solution containing 204 +/- 14 g of carbohydrate (W+C); 3) 204 +/- 14 g of carbohydrate in only 0.49 +/- 0.03 liter of solution (C); and 4) 0. 37 +/- 0.02 liter of water with no carbohydrate (placebo; Pl). These treatments were randomized, disguised, and presented double blind. At 26 min of exercise, P(max) was similar in all trials. From 26 to 116 min, P(max) declined 15.2 +/- 3.3 and 14.5 +/- 2.1% during C and Pl, respectively; 10.4 +/- 1.9% during W (W > C, W > Pl; P < 0.05); and 7.4 +/- 2.2% during W+C (W+C > W, W+C > C, and W+C > Pl; P < 0. 05). As an interesting secondary findings, we also observed that carbohydrate ingestion increased heat production, final core temperature, and whole body sweating rate. We conclude that, during prolonged moderate-intensity exercise in a warm environment, ingestion of W attenuates the decline in P(max). Furthermore, ingestion of W+C attenuates the decline in maximal power more than does W alone, and ingestion of C alone does not attenuate the decline in P(max) compared with Pl.

Administration, Oral↗

PubMed2000

Effectiveness of a cardiovascular health promotion education intervention on the attitudes of urban African American school-age children.

African American children are at risk for high rates of morbidity and mortality associated with cardiovascular (CV) disease as they become adults, yet little is known about the effectiveness of CV risk-reduction interventions in African American children. This study explored the effectiveness of a concentrated CV health promotion educational program on health-related attitudes of 76 African American children enrolled in a mid-southern school system. The Children's Cardiovascular Health Promotion Attitude Scale was used to examine differences in attitude prior to and 2 weeks following a focused health education intervention. Results demonstrate that children have preconceived attitudes regarding practice of health behaviors and that these attitudes are modifiable with age and developmental level specific educational interventions. Findings indicate the need for health care providers to assume more active roles in reducing the risk of future CV disease and death in African Americans through health promotion education of individuals who influence the development of children's attitudes.

Black or African American↗

PubMed2000

Relationship between cerebral perfusion in frontal-limbic-basal ganglia circuits and neuropsychologic impairment in patients with subclinical hepatic encephalopathy.

UNLABELLED: Early detection of neuropsychologic impairment in cirrhotic patients with subclinical hepatic encephalopathy (SHE) is important for their prognosis and quality of life. Abnormal MRI and MR spectroscopy (MRS) findings have been proposed as early markers of brain damage in these patients, but the role of functional neuroimaging in this field still has to be defined. In this study, the SPECT perfusion pattern in patients with SHE was investigated, and the relationship between regional cerebral blood flow (rCBF) and the MRI, MRS, neuropsychologic evaluation and biochemical data of these patients was assessed. METHODS: Data were obtained from 13 cirrhotic patients with SHE and 13 age-matched healthy volunteers. Fasting venous blood ammonia and manganese sampling and a battery of standardized neuropsychologic tests related to basal ganglia function and sensitive to the effects of liver disease were all performed on the same day. MRI and 99mTc-hexamethyl propyleneamine oxime SPECT were performed within 2 wk. RESULTS: A pattern of decreased prefrontal rCBF was found in patients with SHE compared with healthy volunteers. Basal ganglia and mesial temporal rCBF correlated inversely with performance on motor tasks involving speed (Purdue pegboard test) and frontal premotor function (Luria graphic alternances and Stroop tests). Thalamic rCBF correlated positively with T1-weighted MRI signal hyperintensity in the globus pallidus and with abnormal MRS findings. Neither the MRI signal intensity of the globus pallidus nor MRS correlated with neuropsychologic test results. CONCLUSION: Cirrhotic patients with SHE show a SPECT pattern of impaired prefrontal perfusion that does not seem to account for their neuropsychologic deficits. On the other hand, perfusion in some parts of the limbic system and limbic-connected brain regions, such as the striatum and the mesial temporal regions, increased with neuropsychologic impairment. These findings suggest that brain SPECT may be more sensitive than MRI in delineating cirrhotic patients requiring in-depth clinical testing to reveal basal ganglia-related neuropsychologic alterations.

Basal Ganglia↗

PubMed2000

Embryonic regulation of endometrial molecules in human implantation.

Embryonic implantation requires co-ordinated development of the blastocyst and the maternal endometrium. Considerable advances have been made in understanding the cell biology of these partner tissues separately. Nevertheless, communication between these tissues and the reciprocal effects of these tissues on each other constitutes an exciting and as yet unsolved paradigm in reproductive medicine. Crosstalk between the embryo, endometrium and the corpus luteum is known to occur in ruminants and primates, and, more specifically, endometrial-embryonic interactions are reported in rodents and primates. In this review, an in vitro model for analysing the interactions between human endometrial epithelium and blastocyst in the adhesion phase of embryonic implantation is presented. The results of investigations of embryonic regulation of endometrial epithelial molecules such as adhesion molecules, mucins, chemokines and cytoskeleton proteins are also presented.

Blastocyst↗

PubMed1999

Thymic carcinoid and parathyroid hyperplasia detection with 99mTc-MIBI men type 1.

We report a case of a 35-year-old male, with a history of diarrhea, renal lithiasis with frequent expulsions of calculus and hypercalcemia during the last 2 years. The patient was studied and diagnosed with a multiple endocrine neoplasia type I (MEN I), familiar (mother with MEN I). A scintigraphic study with 99mTc-MIBI was performed in order to localize hyperfunctioning parathyroid glands because of biochemical diagnosis of primary hyperparathyroidism. Double phase 99mTc-MIBI scan detected one hyperfunctioning parathyroid gland and a large anterior mediastinal mass. Subsequent, plain radiograph and CT of the chest showed a soft-tissue mass in that localization. Punch biopsy of the lesion guided by CT revealed malignant cells of neuroendocrine tumor. The tumor was removed and histologically confirmed as a carcinoid within a thymus in a MEN type I syndrome. MEN I patients can benefit from the examination with this agent which can potentially localize not only parathyroid endocrine pathology but also unknown associated tumors.

Adult↗

PubMed1999

Radial bone mineral density and estimated rates of change in normal Scottish women: assessment by peripheral quantitative computed tomography.

This study examines normative bone mineral density (BMD) data, as measured by peripheral quantitative computed tomography of the ultradistal radius, in 332 Scottish women aged 18-90 years, comparing it to a recently reported normal German population. The normative Scottish data were higher in almost all decades compared with German counterpart, percentage differences being +0.002%-+21.6% for total (Qtot), and -0.06%-+31.9% for trabecular (Qtrab) BMD. Differences in calibration of the Stratec XCT-960 and XCT-900 systems are thought to be largely responsible for these differences. Estimated age-related changes were determined in the Scottish population. A cubic regression model best fitted age-related changes in the whole population, and changes as a function of years postmenopause in the postmenopausal subgroup, for Qtot, subcortical (Qscort), and cortical (Qcort) BMD, whereas a parabolic regression model best fitted corresponding changes in Qtrab BMD. Percentage age-related changes (5 years: 10 years postmenopause) in Qtot (-0. 79%-1.12%/year) and Qscort (-0.72%-1.12%/year) were greater than Qtrab (-0.53%-0.56%/year) in the early postmenopausal years. Maximum age-related changes were found at 20 years postmenopause for Qtot (-1.36%/year), Qscort (-1.39%/year), and Qcort (-1.39%/year). This study has highlighted variation in normative data derived by different Stratec pQCT systems. The estimated age-related changes suggest that early postmenopausal bone loss preferentially affects subcortical rather than trabecular bone at the radius.

Adolescent↗

PubMed1999

Geometry of conjugated double bonds of CLA isomers in a commercial mixture and in their hepatic 20:4 metabolites.

Rats were fed a fat-free diet for 2 wk. After this period, while maintaining the animals on the same diet, the rats were given intragastrically 180 mg per day of a mixture of conjugated linoleic acids (CLA) as triacylglycerols. Gas chromatography mass spectrometry (GC-MS) analyses of this mixture, as well as hydrazine reduction and GC-MS and GC-Fourier transform infrared analyses of the resulting monoenes, revealed the presence of two major isomers, the 9c,11t- and the 10t,12c-18:2 accompanied by smaller amounts of the 8t, 10c and the 11c, 13t-18:2 isomers. Minor quantities of cis,cis and trans,trans conjugated isomers also were detected. The total fatty acid methyl esters from the liver lipids were fractionated by reversed-phase high-performance liquid chromatography, and the fraction containing the 20:4 isomers was further fractionated by silver nitrate thin-layer chromatography. A band containing two 20:4 conjugated isomers was submitted to hydrazine reduction and the resulting monoenes analyzed by GC-MS as dimethyl-oxazoline derivatives. The two conjugated isomers were tentatively identified as 5c,8c, 11c, 13t-20:4 and 5c,8c,12t,14c-20:4. These could be formed by desaturation and elongation of the 9c,11t- and 10t,12c-18:2 present in the commercial CLA mixture.

Animals↗

PubMed1999

Towards prediction and modulation of treatment response.

The purpose of this paper is to evaluate new predictive assays and their potential to modulate treatment response. Their impact is presented in the context of three EORTC clinical trials in head and neck, lung and breast cancer, showing an improvement in survival by accelerated fractionation, concomitant use of cisplatin and radiotherapy and adjuvant hormonal treatment, respectively. Assays have been developed to predict the response to treatment by measuring tumor characteristics, such as the growth potential by the labeling index after i.v. injection of IdUrd, the extent of radiation-induced stable and unstable chromosome aberrations and the induction of apoptosis. These assays could guide us in the adaptation of the individual radiation doses and fractionation schedules. The measurement of the effect of cisplatin on DNA has become feasible with the development of antibodies against DNA adducts. In a recently completed phase II dose escalation trial with concomitant radiotherapy and daily cisplatin in lung cancer, we found that patients with high DNA adduct levels measured in the buccal mucosa, had a much better survival rate than patients with a low or undetectable amount of cisplatin DNA adducts. A better understanding of the signal transduction pathways involved in radiation-induced apoptosis may help to design studies aimed at modulating the apoptotic response. We and others have recently shown that alkylphospholipids, which inhibit mitogenic signaling, induce apoptosis in a variety of tumor cell lines. In combination with ionizing radiation, these compounds cause an enhancement of apoptotic cell kill. This type of signaling-based intervention study may form the basis for new therapeutic strategies. Pretreatment levels of apoptosis may be helpful in predicting treatment outcome, although the data so far show inconsistent results. The importance of evaluating other tumor-biological parameters, including cell kinetics should be stressed. Based on assays predicting reliably the response to hormonal therapy, a more appropriate choice can be made for therapeutic intervention with hormonal therapy and for selecting the appropriate adjuvant therapy in breast cancer patients. The development of a functional estrogen receptor assay (ER-FASAY), based on a yeast growth-assay, provides a way of estimating abnormal function of the receptor in tumors with a positive estrogen receptor score as measured by a classical immuno-histochemistry assay. This yeast assay can also detect different DNA mutations of the estrogen receptor existing in an individual tumor specimen.

Antineoplastic Agents↗