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H A Hopkins

Publications and source records attributed to H A Hopkins.

At least 19 recordsLinked to original sources
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.

Animals↗
PubMed1978

Solid tumour models for the assessment of different treatment modalities: VII: single vs fractionated doses of 5-fluorouracil on two solid tumours and their hosts.

The effects of one large single dose of 5-fluorouracil (FU) have been compared to the same amount given in divided doses daily over a 3- or 5-day period. Comparison of the effects of single vs fractionated dosage was made on 2 types of experimental solid tumour with different growth, cell kinetic, histological and metastasizing properties. The tumour response was essentially the same for both the single and fractionated dose schedules.There were marked increases in animal mortality from drug toxicity following fractionated doses of FU compared to one large single dose. Mortality in animals with Tumour 3924A increased from 10% following one large single dose to 60% for animals given daily fractionated doses for 3 days, and 80% for animals given daily fractionated doses for 5 days. Total marrow reserve was measured by the total DNA content of tibial marrow. The nadir of 6 days for loss of total tibial marrow DNA following one large dose of FU was increased to 9 days for both fractionated schedules of FU. The 3-day delay in recovery of the marrow prevented recovery within the time frame necessary for animal survival. The inference from these experimental cancer-treatment studies is that daily fractions of chemotherapeutic agents such as FU result in increased morbidity and mortality, without benefit in the control of the solid tumour. The results question the advisability of the clinical practice of initially giving small daily "loading doses" of proliferation-dependent agents such as FU.These results emphasize the need for more precise information on the temporal relationship between the response and recovery of the host and the response and recovery of the solid tumour. They also emphasize the need for a better clinical understanding of the time sequence of solid-tumour recovery in relation to the time sequence of marrow recovery.

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PubMed1978

Response kinetics of host and experimental solid tumour after adriamycin.

The effects of adriamycin (Adr) on the solid-tumour model, hepatoma 3924A, and on critical organs of the host, were determined at intervals after single injections of 60 mg/m2 of the agent. A reduced rate of tumour growth was evident 4 days after treatment, continued to Day 11, and then returned to rates comparable to control values. On Day 11 tumour volumes of treated animals were 38% of control. During the period of reduced growth, 3H-TdR incorporation into tumour DNA and percentage labelled tumour cells were less than control values. DNA concentration in tumour was not affected by drug treatment, which differs from observations made in other studies employing 5-fluorouracil (FU). No evidence of significantly increased necrosis or fibrosis of the tumour was found after Adr. The Adr treatment caused loss of 60% of the tibial marrow by Day 4, as measured by total DNA content. Marrow DNA recovered to control levels between Days 7 and 11. Incorporation of 3H-TdR into heart DNA was reduced more than 40% during the first week after Adr treatment; enhanced incorporation was observed on Day 11, and control levels were attained by Day 17. No significant pathological evidence of cardiac toxicity was found 2-21 days after Adr but degeneration of myocardial cells and oedema was prominent at 14 weeks.

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PubMed1977

Solid tumor models for assessment of different treatment modalities: therapeutic strategy for sequential chemotherapy with radiotherapy.

A therapeutic strategy for combined radiotherapy and chemotherapy of experimental solid tumors has been devised. More effective utilization of combined chemotherapy and radiotherapy may be realized clinically if comparable information is obtained in man. The overall treatment efficiency of successive courses of treatment has been determined by a method that defines tumor response quantitatively over an entire spectrum of tumor responses. The findings of this study have shown that an individual tumor that responds well to the first course of therapy will respond well to the second and third courses of combined modality therapy. Various solid tumors in different animal species have demonstrated variability of response to treatment, analogous to the many types of response found clinically.

Animals↗
PubMed1977

Properties of the H-4-II-E tumor cell system. II. In vitro characteristics of an experimental tumor cell line.

The growth and cell proliferation characteristics of the H-4-II-E cell line, giving rise to hepatoma H-4-II-E when inoculated into male ACI rats, were studied in vitro. Following seedling of 2 x 10(5) cells into culture dishes, exponential cell growth occurs in cultures fed both at 24 hr and 48 hr intervals with a population doubling time of 18-4 hr. Plateau phase growth conditions are established on day 7 and day 5 for cultures fed at 24 hr and 48 hr intervals respectively. Both the plateau phase cell density and the maintenance of plateau phase appear dependent on the frequency of feeding. For cultures fed daily, the transition from exponetial growth to plateau phase results from both a reduction in the number of proliferating cells (99% v. 35%) as well as an elongation of the cell cycle (17-7 hr v. 128-4 hr). The cell proliferation characteristics of the culture are further discussed in reference to both cell growth and feeding schedules of other cell lines.

Animals↗
PubMed1977

Cell proliferation in organs of rats bearing hepatoma 3924A: effects of X-rays of surgery.

For inbred rats with Morris hepatoma 3924A, increases in tumor size were accompanied by increases in weight and DNA content of spleen, DNA content of tibial marrow, and peripheral white cell concentrations of blood. White blood cell concentrations of rats with tumors weighing more than 5 g were approximately two-fold greater than for rats without tumors. Neutrophils were primarily responsible for the increase in white cells. Local x-radiation of 3750R to the tumor when the tumor was small prevented tumor growth and the increases in spleen weight, incorporation of 3H-thymidine into spleen DNA, white blood cell count, and tibial marrow DNA content related to tumor growth. Surgical removal of large tumors resulted in a return of spleen weight and DNA content to near normal values within 1 week. Despite the evidence for increased cell proliferation in hematopoietic tissues of rats with hepatoma 3924A, no systematic relationship has been observed between tumor size and animal survival following treatment with the cell cycle specific agent 5-fluorouracil when tumors have varied in size from 0.5 g to 5 g at the time of drug treatment.

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PubMed1976

Solid tumour models for the assessment of different treatment modalities: IV. the combined effects of radiation and 5-fluorouracil.

Neither radiation alone (375 to 1500 rad) nor5-fluorouracil (FU) alone (50-250 mg/kg) is sufficient to prevent an increase in the volume of the solid tumour model hepatoma 3924A. However, as little as 750 rad with 100 mg/kg FU can reduce the tumour below the volume at the time of treatment for as long as 14 days. A series of combined FU and radiation doses given every 11 days should then result in successively smaller tumour volumes until the tumour is eradicated. Changes in tumour volume were analysed by two different methods: (1) tumours in each treatment mode were grouped together and the average response to treatment determined, and (2) tumour volume changes in individual tumours were analyzed utilizing the chi2 technique, which fits the logarithmic tumour volume change with time to polynomials. This two-directional method of analysis has the advantage of permitting both an overview of the main effects of treatment via the averages, and at the same time a detailed examination of the mechanism by which these effects occur through the analysis of individual response. The results suggest that, in addition to concentrating on the cellular response immediately after therapy, greater emphasis should be placed on the kinetic changes of the tumour 1-3 weeks after single or multiple modality therapy. These findings demonstrate how the sequencing of single and/or combined treatment modalities may be investigated in order to detemine how best to obtain maximum effects of treatment on different types of tumours following recovery of the host from the previous treatment series.

Animals↗
PubMed1976

Solid tumor models for the assessment of different treatment modalities: systematics of response to radiotherapy and chemotherapy.

The change of tumor volumes (efficiency) with local tumor radiation doses from 375R to 3750R and 5-fluorouracil (5-FUra) from 50 to 250 mg/kg was assessed in rats bearing hepatoma 3924A. The data were analyzed utilizing a chi2 technique which fits the logarithmic volume response to polynomials. This provided greater flexibility in selecting different mathematical forms, and allows more accurate description of tumor changes after treatment than the least squares analysis previously used. Quantitative information can be obtained on one tumor following treatment by this method. This information is more analogous to the management of a patient with a solid tumor. The results show a continuous increase in efficiency of radiation throughout the radiation dose range from 375R to 3750R. The efficiency of 5-FUra increased slightly but did not continue to increase with doses of 5-FUra higher than 150 mg/kg. This suggests that factors such as toxicity to the host may prevent further increases of the effectiveness of 5-FUra. The time of minimum tumor volume change after radiation was approximately 6 days and for 5-FUra, 6 days. The time for maximum tumor volume change for 5-FUra was 12 days. There was a slight trend upward for maximum growth for increasing radiation doses from 18 to 22 days. The time of occurrence of both minimum and maximum tumor volume change after treatment showed little relationship to increasing doses of radiation and 5-FUra. Parallel studies have shown that the maximum rate of tumor volume change occurs shortly after the recovery of the host from the effect of 5-FUra. It is feasible, therefore, to use chemotherapy alone or in combination with radiotherapy, and optimize the scheduling of these treatment modalities with recovery of the host from previous therapy.

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PubMed1976

Changes in cellularity induced by radiation in a solid tumour.

The growth, and cellular responses of Morris hepatoma 3924 A to a locally-administered dose of 3750 R X-rays were studied using the following parameters; (1) relative tumour volume changes; (2) tritiated thymidine (3H-TdR) incorporation into DNA; (3) tumour DNA content and (4) cellular analysis, including 3H-TdR labelling index, mitotic index, aberrant mitotic frequency and relative cell density. Before depression of tumour growth, cell proliferation is temporarily interuppted. As proliferation is reinitiated, a short-lived synhcrony and prolongation of cell-cycle traverse are reflected in (a) the labelling index and mitotic index, (b) the relative cell density, and (c) the rate of incorporation of 3H-TdR into DNA. Within 4 days after radiation, cell proliferation and 3H-TdR incorporation are significantly depressed. Simultaneously there are reductions in both the relative cell density and tumour DNA contents, and these remain depressed as the tumours initiate regression. From these studies, it is apparent that the cellular responses to radiation insult occur well in advance of measurable volume changes and are observed both in tumours that continue to regress and in those that initiate regrowth.

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