Biomedical subjects

H A Hopkins

Publications and source records attributed to H A Hopkins.

At least 37 records · Page 2Linked to original sources

PubMed1983

Solid tumor models for the assessment of different treatment modalities. XXI. Comparison of different radiation dose schedules alone or in combination with cyclophosphamide.

Total radiation (4500 rad) and cyclophosphamide doses (450 mg/kg or 2.7 g/m2) were held constant over a 24-day period in rat hepatoma 3924A using radiation schedules in which 1500 rad were given over a 1- to 2-day period in 1-8 fractions, repeated at 11-day intervals, with or without cyclophosphamide. Reducing the rad per fraction resulted in a reduced incidence of complete tumor response and tumor cures, and a reduction in the magnitude of skin response. Cure rates were 40, 10, 0, and 0%, respectively, for the 1500, 750, 500, and 250 rad per fraction groups without cyclophosphamide. When the 1500, 750, 500, 375, 250, and 188 rad per fraction groups were given 150 mg/kg cyclophosphamide day 1 after radiation, major increases occurred in tumor cures, with the cure rates being 80, 80, 80, 70, 60, and 50%, respectively. The addition of cyclophosphamide did not significantly alter skin reaction to radiation. The higher rad per fraction schedules were more effective in controlling metastatic dissemination when radiation was used alone. The addition of cyclophosphamide markedly reduced metastatic dissemination in both high and low-dose per fraction schedules. Optimal treatment levels were estimated from analysis of fitted response surfaces, and the quantitative interrelationship between normal tissue reaction, probability of tumor cure, and associated relative hazard to the host estimated from the results of these analytical methods. Hyperfractionated radiation dose schedules with dose/fraction in the clinical range combined with cyclophosphamide can significantly increase the therapeutic ratio and prevent metastatic dissemination compared with radiation alone as a result of the increased effectiveness of combined modality therapy on the tumor, without a concomitant increase in normal tissue reaction.

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PubMed1983

Response of cell populations in tumor cords to a single dose of cyclophosphamide or radiation.

We have examined tumor cords of hepatoma 3924A in rats treated by 15 Gy of X-rays or 150 mg/kg of cyclophosphamide. Parameters measured were: cord thickness, cellular density, [3H]-TdR LI, MI and proportion of necrotic cells within the cord. With cyclophosphamide, a drop in cell density of 40% and in LI of 60% did not cause shrinkage of the cords. During the recovery phase, increase in cell number coincided with changes in the kinetics of the cell population adjacent to the capillary. For X-rays an approximately 10% decrease in cord thickness was associated with a rapid reduction in cell density and a relatively poor proliferative response of the cells adjacent to the vessel. There was little evidence for the sparing of remote cells with either agent. It did not appear that the progression of cells across the cord would be interrupted sufficiently for any 'spared' remote cells to participate in the therapeutic response.

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PubMed1983

Comparison of effects of daily versus hyperfractionated split-course radiation schedules with and without cyclophosphamide on median survival, metastatic dissemination, tumor cure, and growth rates.

Daily fractions of 188, 250, 375, 500, and 750 rads were given to rats with hepatoma 3924A so that all groups received the same weekly dose of 1500 rads over a 6-week period, for total doses of 9000 rads when only radiation was given and 4500 rads when combined with cyclophosphamide. No tumors were cured (with two exceptions) with or without three doses of cyclophosphamide (150 mg/kg or 0.9 g/sq m) given 14 days apart. The addition of cyclophosphamide to the daily radiation treatment schedules did not change the time for tumors to reach 8 times the volume at time of treatment but did result in a longer median survival, which was attributed to a reduction of pulmonary metastases. A hyperfractionated radiation schedule using six 250-rad fractions given three times daily every 4 hr for 2 days combined with cyclophosphamide (150 mg/kg) 1 day later and repeated two additional times at 11-day intervals for a total dose of 4500 rads and cyclophosphamide (450 mg/kg) resulted in eradication of six of ten tumors, for a cure rate of 60%. Skin damage, determined by visually scoring the skin, appeared to be fully recovered by Day 126 and remained so until the end of the experiment on Day 384. The three courses of hyperfractionated radiation (total dose, 4500 rads), when given alone, were ineffective in producing tumor regression and cure. Combining cyclophosphamide with hyperfractionated split-course radiation schedules gave a major increase in tumor cure rate as compared with radiation alone at the same (4500 rads) or higher (9000 rads) doses. The major gains in effective utilization of the two modalities is greatly diminished or lost when the radiation is administered as daily fractions.

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PubMed1982

In vivo tumour-cell proliferation after adriamycin treatment.

Adriamycin (10 mg/kg) administered s.c. to male ACI rats bearing Hepatoma H-4-II-E caused a 9-day delay in tumour growth but no changes in the clonogenic fraction of the tumour were detectable by in vitro assay at any time after treatment. There is no significant decrease in the yield of cells on enzymatic dissociation of the tumour nor a reduction in mg DNA/g tumour that might indicate a decrease in tumour cellularity. Mitotic and labelling indices and [3H]dT uptake into DNA remain essentially unchanged, relative to age-equivalent controls, but are slightly lower than in controls of equal weight. The reliability of the clonogenic assay and possible mechanisms by which Adriamycin delays tumour growth are discussed.

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PubMed1982

Solid tumor models for the assessment of different treatment modalities. XIX. Tumor cure rates and tumor control following sequential administration of radiation and cyclophosphamide.

Tumor cure rates greater than 50% have been realized by the administration of three and four series of 1500 rads radiation and 150 mg/kg (0.9 g/m2) cyclophosphamide which were separated by 1, 7. or 11 days. Increasing the time between treatment modalities from 1 to 7 and 11 days provided a 2- to 3-week recovery period for each treatment modality without a reduction in cure rates. However, the mean time for complete response increased from 24.8 +/- 17 days for 1 day, 30.7 +/- 3.0 days for 7 days, and 38.3 +/- 4.8 days for 11 days between treatment modalities. Giving the second series of radiation and cyclophosphamide on days 16 and 17 resulted in a cure rate of 50%. Increasing this interval to 21-22 days resulted in no cures. The results of giving each modality alone at 11-day intervals have been compared with results of altering administration of the two modalities at 11-day intervals. Comparing the three regimens where a treatment was given every 11 days, the numbers of animals with cures were 0 of 10 for cyclophosphamide alone, 2 of 10 for radiation alone, and 5 of 9 for alternation of the two treatments every 11 days. Well-defined periods of accelerated growth occur between 10 and 20 days after administration of single doses of either radiation or cyclophosphamide. The increased effectiveness of alternate utilization of the two modalities suggests that prior treatment by one modality increases tumor sensitivity to the second modality.

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PubMed1982

Cyclophosphamide-induced cardiomyopathy in the rat.

Cyclophosphamide given to ACI inbred rats produced histologic evidence of cardiomyopathy and degenerative vascular changes beginning as early as 4 days after the first of three 150-mg/kg doses (0.9 g/m2). The interval between doses was 14 days to allow bone marrow to recover after each treatment. Twofold increases in heart weight and DNA content were observed 56 days after initial treatment; compensatory hypertrophy and a marked infiltration of the myocardium by lymphocytes were observed histologically at that time. Heart weight and DNA content were again at control levels on Day 126. Hydroxyproline content, which increased along with DNA and weight, did not decrease until after Day 196, confirming a morphologic finding of increased fibrosis after cyclophosphamide which eventually decreased in severity. These data re-emphasize the necessity for considering both the acute and chronic toxic effects, as well as recovery, when developing treatment schedules employing therapeutically effective chemotherapeutic agents.

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PubMed1981

Solid tumor models for the assessment of different treatment modalities: XVI. Sequential combined modality (Cyclophosphamide-Radiation) therapy.

A tumor cure rate of 60% was realized when three series of combined radiation (1500 rads) and cyclophosphamide (150 mg/kg) doses were given sequentially to rats with hepatoma 3924A and the time between modalities held constant at 7 days. This sequence was previously shown to enhance tumor sensitivity and diminish host toxicity. The first series was given on days 0 and 7; second, days 14 and 21; and third, days 28 and 35. The cure rate was reduced to 10% when the time of the second series was increased from 14 to 32 days (first series, days 0 and 7; second, days 32 and 39; and third, days 63 and 70). No cures were obtained when the time of the second series of combined cyclophosphamide and radiation was further increased from 14 to 40 days; however, this treatment schedule resulted in at least a threefold increase in life span over controls of 30 +/- 1 days. Two and three single 1500 rad doses of radiation given 14 to 40 days apart produced skin changes within accepted limits of normal tissue tolerance. No major long-term hematological changes in peripheral blood and bone marrow have been demonstrated to date following two and three courses of cyclophosphamide given 14 to 40 days apart. Experimental results indicate that the frequency and dosage of cyclophosphamide and radiation used are within clinically acceptable doses and scheduling.

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PubMed1980

Solid tumor models for the assessment of different treatment modalities. XIII. Comparison of response and recovery of host and solid tumor to cyclophosphamide and radiation.

A study of the effects of local tumor radiation alone (1500R) and cyclophosphamide alone (150 mg/kg) on the experimental solid tumor rat hepatoma 3924A has been completed. Cyclophosphamide was more effective in controlling tumor growth than either radiation or 5-fluorouracil (5-FU) (150 mg/kg) previously reported. Parallel recovery of bone marrow with increasing animal survival in "split dose" cyclophosphamide toxicity studies (as with 5-FU) indicates that bone marrow is the critical organ for sequential chemotherapy. Recovery of intestinal mucosa following cyclophosphamide (and 5-FU) occurred much earlier than recovery of bone marrow, substantiating the fact that bone marrow is the critical organ governing the time of administration of a second series of chemotherapeutic agents. The longest period of time (seven days) between delivery of radiation and administration of cyclophosphamide resulted in the most effective use of the two modalities. Tumor growth delay was 1.2 times greater than the additive effects of each agent given alone. Radiation and cyclophosphamide given at other time intervals resulted in either an additive or less than additive effect. One of the greatest difficulties to overcome in the more effective clinical use of combined modality therapy is increased toxicity. In these studies, the least host toxicity occurred when the effects of combined radiation and cyclophosphamide on the tumor were greatest. Results of experimental studies to date suggest that sequential combined modality therapy may be given at a time of maximum tumor growth rate that occurs following the previous treatment series. Since the time of maximum tumor growth rate occurs after recovery of the bone marrow from the previous treatment series, combined chemotherapy-radiotherapy schedules of this type should permit sequential administration of chemotherapeutic agents, such as 5-FU and cyclophosphamide, at the time of enhanced tumor sensitivity and diminished host toxicity.

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PubMed1980

Response and recovery kinetics of a solid tumour after irradiation.

The effects of local tumour radiation over the dose range 7.5-30 Gy on the growth and cell kinetics of rat hepatoma H-4-II-E have been investigated. A plot of growth delays against log surviving fraction was linear below a fraction of 0.03, but failed to extrapolate to the origin. Following a single dose of 15 Gy to the tumour, DNA-precursor incorporation, labelling and mitotic indices were depressed for 7 days. Tumour cellularity, measured as DNA/g tumour, was reduced and the rate of increase of total clonogenic cells slower than after complete tumour recovery. From Day 7 to Day 9 all indices of proliferation recovered to about control levels, clonogenic cell numbers increased more rapidly and tumour cellularity was restored. Repopulation of the tumour therefore appeared to take place mainly after Day 7. Incorporation of [3H]-TdR into tumour DNA reached twice the control values on Day 9. The rate of tumour growth accelerated after the initial decrease, and maximum tumour growth rate was also twice the control values on Day 13. Accelerated growth rates in irradiated tumours, above those of control tumours, occurred 10-16 days after treatment. The effectiveness of sequential therapy may therefore be improved if given during this period of of accelerated tumour growth.

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PubMed1980

Dynamic histology of a rat hepatoma and the response to 5-fluorouracil.

The cellular response of the rat hepatoma 3924A to a single intraperitoneal injection of 5-fluorouracil has been measured in respect of the spatial relationship of the cells to the tumour microvasculature. In this tumour the parenchyma is arranged in cords approximately 150 micron thick around central capillaries. For untreated tumours, those cells at distance less than 80 micron from the capillary had a mean [3HTdR labelling index of 39% and a mitotic index of 2.1%, while for those cells more than 80 micron away the values were 14% and 0.8% respectively. Two days after 150 mg/kg of 5-fluorouracil, mean cord thickness was reduced by 25% and did not recover to the control level until 11 days after treatment. This was also true for the mitotic index. Recovery of the labelling index was complete 2 days earlier. Although absolute values of parameters were different in the populations adjacent to and remote from the capillary, the time course of recovery was similar, with a 'growth spur' 7 to 9 days after treatment. The results from this histologically-based assay have been compared with those from biochemical/biophysical assays that sample the overall tumour population.

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PubMed1980

Changes in growth rate of an experimental solid tumor following increasing doses of cyclophosphamide.

Well-defined times for minimum and maximum growth rates of rat hepatoma 3924A were found when cyclophosphamide doses were increased from 50 to 250 mg/kg. Minimum growth rates occurred 8 to 10 days after treatment and maximum growth rates occurred 13 to 16 days after treatment in 5 groups of 10 animals each that received 50, 100, 150, 200, and 250 mg of cyclophosphamide per kg. Tumor growth delay increased from 6 to 18 days when the dose was increased from 50 to 250 mg/kg. The accelerated growth rate of treated tumors on Day 14 after cyclophosphamide (150 mg/kg) was more than twice that of controls on the same day, 0.349 +/- 0.030 (S.E.) (day-1) and 0.156 +/- 0.011 (day-1), respectively. In addition, the accelerated growth rate of treated tumors on Day 14 was greater than that of controls at initiation of treatment, 0.298 +/- 0.026 (day-1) on Day 2. Increased DNA synthetic rate precedes increased tumor cell proliferation, which, in turn, increases tumor volume. Thus, biochemical studies demonstrating increased cellular proliferation confirm accelerated tumor growth following treatment.

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PubMed1980

Erythrocyte polyamine levels in rats with H4IIE hepatomas before and after radiation treatment.

The concentration of the polyamines, spermidine and spermine associated with the erythrocytes of rats with H-4-II-E hepatomas increased with tumor growth. Following radiation therapy the erythrocyte spermidine and spermine levels decreased by 63 and 47% respectively. Six days after radiation treatment the erythrocyte polyamines had increased to the pre-treatment elevated levels. These data suggest that erythrocyte polyamine levels may be useful in assessing the response to therapy and in detecting the continued growth of the tumor in patients with malignant disease.

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PubMed1979

Solid tumor models for the assessment of different treatment modalities: VIII. The scheduling of treatment for a chemotherapeutically resistant experimental solid tumor.

Single, large doses of adriamycin, cyclophosphamide and 5-fluorouracil (5-FU) have been compared to the same amount of drug given in divided doses daily over a 3 or 5 day period in a solid tumor model which metastasizes to the regional lymph nodes and lungs. No significant increase in life expectancy occurred following adriamycin or cyclophosphamide. However, a significant reduction in life expectancy occurred after 5 fractionated doses of 5-FU but not after the large single dose. The increase in mortality following fractionated doses of 5-FU is attributed to the prolongation of the onset of recovery of bone marrow. Tumor volume reduction following a single dose of each agent was equal to or greater than the fractionated doses. The results of these studies on this chemotherapeutically resistant solid tumor indicate that small daily fractionated doses of adriamycin, cyclophosphamide or 5-FU result in increased morbidity and mortality without therapeutic benefit in tumor control. The time sequence of recovery of the limiting organ of the host (i.e., bone marrow) is similar to the time sequence of recovery of the tumor. Large intermittent single doses of chemotherapeutic agents given following recovery of the host from a previous treatment would be expected to be less toxic to the host and equally effective in control of tumor growth. None of the 3 chemotherapeutic agents was successful in tumor eradication. Previous studies of this series have shown that the utilization of sequential chemotherapy combined with radiotherapy can be successfully used for eradication of another solid tumor which did not metastasize. A similar therapeutic strategy using sequential combined modality therapy should also be effective in the control of the primary H-4-II-E tumor as well as its metastatic dissemination. Information gained from these experimental studies should eventually provide information which should be helpful in the clinical management of chemotherapeutically resistant solid tumors in man.

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PubMed1979