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Biomedical subjects

J E Byfield

Publications and source records attributed to J E Byfield.

At least 37 records · Page 2Linked to original sources
PubMed1983

Phase I-II study of 120-hour infused 5-FU and split-course radiation therapy in localized non-small cell lung cancer.

Thirty patients with locally advanced nonresectable non-small cell bronchogenic carcinoma were studied for tolerance and response to 120-hour continuously infused 5-FU (IFU) combined with chest x-ray therapy. The IFU was escalated in patient groups from 20 to 35 mg/kg/24 hours. Radiation was also escalated in patient subsets from 200 to 400 rads/fraction using a split-course technique to a total dose of 5000 rads. Tolerance was exceeded by IFU doses of 35 mg/kg/day. The complete response rate was ten of 28 patients (36%); a complete response was associated with a significantly prolonged survival. Radiosensitization of lung cancer by IFU appears clinically feasible in man.

Aged↗
PubMed1982

Intra-arterial chemotherapy using an implantable infusion pump and liver irradiation for the treatment of hepatic metastases.

Liver metastases are a common cause of death in colon carcinoma. The dual blood supply of the liver permits regional perfusion while hepatic catabolism fo 5-fluorouracil (FU), floxuridine (FUdR) permit higher drug exposures than systemic (IV) administration. We have studied the effect of continuous intra-arterial chemotherapy (FU: 5-10 mg/kg/day and FUdR: 0.2 mg/kg/day) and whole liver irradiation (1000 rad every 4 weeks, total dose of 3000 rad) for metastatic colon carcinoma to liver. Eighteen patients with metastases to liver only are reported using this combination therapy. Seven patients had percutaneous placement of a catheter via the brachial artery, two had operative placement of a catheter via the gastroduodenal artery, all of which were connected to the Cormed infusor system, nine had operative placement of the Infusaid implantable pump with catheter placement into the hepatic artery via the gastroduodenal artery. The median survival for the entire group was 241 days. In those patients whose liver function tests (bilirubin and alkaline phosphatase) were less than two times normal, the median survival was 770 days. The median survival of the patients with greater than two times normal LFT's was 178 days. Two patients died of complications of the treatment. One who developed irreversible radiation hepatitis but at autopsy had only two areas of microscopic tumor foci in the liver and another who had received only 15 days of infusion and 1000 rad to liver. This patient developed irreversible chemical enteritis secondary to chemotherapy infusion into the superior mesenteric artery. Three patients have undergone abdominal reexploration and one at autopsy, who were found to have no gross evidence of tumor in the liver despite previous pathologic confirmation. It appears that some patients with minimal tumor burdens can have sterilization of their tumors. There were three cases of reversible liver function abnormalities. Complications associated with conventional intra-arterial chemotherapy (artery thrombosis, catheter sepsis and dislodgement, pump infusion variation and pump failure) were not seen with the Infusaid delivery system. The pump is refilled every 2-3 weeks via percutaneous puncture. All therapy was given on an outpatient basis. Pump acceptance and tolerance was 100%. Intra-arterial chemotherapy can now be accomplished without the morbidity associated with it in the past. The combination of chemotherapy and liver irradiation may offer improved survival in selected patients.

Adult↗
PubMed1982

Antibody-dependent cellular cytotoxicity-mediated serotherapy against murine neuroblastoma. I. In vitro and in vivo treatment using normal, gamma-irradiated and immune-stimulated rat effector cells.

The in vitro and in vivo activity has been investigated of antisera prepared against a murine (C-1300) neuroblastoma line (MNB) capable of differentiation. An antibody-dependent cellular cytotoxicity (ADCC) reaction was employed using rat spleen cells (RSC). ADCC activity in vitro (using 51Cr-release) was shown, but a maximum of only 50% of the immunologically releasable 51Cr was achieved. Nevertheless, in vivo (syngeneic mouse-tumor flank assay) significant delays were obtained in tumor onset and lethality. Under ideal circumstances, i.e., coating of tumor cells prior to inoculation and high RSC effector cell ratios, a significant number of animals could be cured of substantial tumor burdens (10(6) cells). While close proximity of the site of injection of effector cells was required (ectopic injections of RSC were ineffective), the anti-MNB ADCC was shown to be quite active in vivo without external precoating of the cells with antisera. RCS obtained from BCG-treated rats were more numerous and slightly more effective. RSC obtained from gamma-radiated animals retained normal activity. With appropriate antisera this approach could be useful under selected clinical circumstances.

Adjuvants, Immunologic↗
PubMed1982

Radiation therapy, local tumor control, and prognosis in bronchogenic carcinoma: current status and future prospects.

While the overall prognosis for cure of bronchogenic carcinoma remains poor for most patients, there is a growing body of evidence suggesting that rationally optimized local therapy may benefit a significant subset of patients. Local therapy in this context includes any systemic therapy (such as chemotherapy or immunotherapy) that enhances local tumor control in the chest. Compared with many other human epithelial cancers, the total local tumor burden is large for many nonresectable lung cancers and not within the tolerance for control by radiation alone. Thus there is growing evidence that combined surgery and radiation treatment will improve results, especially in the differentiated tumors. Proper selection of patients is important and must include histologic stratification in addition to conventional TNM staging. It is projected that much useful research can be conducted during this decade using clinical tools now available and those that are being tested in early clinical trials throughout the world. Likely candidates for such improvements are both oxic and hypoxic radiosensitizing drugs that should decrease the death rate from uncontrolled local cancer in the chest.

Carcinoma, Bronchogenic↗
PubMed1982

Bleomycin, cyclophosphamide and radiotherapy in regionally advanced epidermoid carcinoma of the head and neck.

We have treated 24 patients with squamous carcinoma of the head and neck and advanced regional (N2-3) disease. The regimen consisted of 3 cycles, each of 28 days. Cyclophosphamide (1 gm/m2 I.V.) was given on day 1, bleomycin (15 u I.M.) on days 2, 4, 9 and 11, and ionizing radiation (60Co, 180 rad/fraction) days 1-5, and 8-12. No therapy was given on days 13-28. After three cycles of therapy, 13 patients had a complete response; following further therapy (surgery, interstitial or external beam radiation), 16 patients were free of disease. However, remissions were not durable and 11/16 patients recurred loco-regionally with a median time to recurrence of 5 months; most (7/11 also developed distant metastases. These patients have biologically aggressive disease and may have a worse prognosis than patients who are Stage IV based on a T4 primary lesion only.

Bleomycin↗
PubMed1982

Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined 5-Fluorouracil or ftorafur and X rays.

The combined effects of X ray and 5-Fluorouracil (5-FU) in tissue culture have been studied using two human adenocarcinoma lines (HeLa and HT-29 cells). Both showed similar sensitivities to 5-FU, HeLa cells appearing somewhat more resistant to higher concentrations. Combined treatment of both cell types with 5-FU and X rays led to a time-dependent enhancement of cell killing ("radiosensitization"). Only post-radiation incubation had any effect, prior exposure to 5-FU being strictly additive. Enhanced cell killing by combined 5-FU and X rays could not be explained by either the infliction of additional acute damage in the immediate post-radiation period or an inhibitory effect of 5-FU on the repair of sub-lethal X ray injury. Rather, the enhanced cytotoxicity proved to be dependent on a damage expressed in time periods exceeding the duration of a cell doubling time in vitro. Overall, the data equally suggest that X rays may sensitize the cells to 5-FU. The enhanced cell killing is maximized if the cells are continuously exposed to 5-FU for 48 hours following the X ray exposure. These results indicate that clinical treatment regimens might be useful in evaluating 5-FU infusional scheduling in accordance with these unique requirements, which are not met by conventional bolus 5-FU and X ray therapy fractionation regimens. Ftorafur, a drug proposed to act as a slow release form of 5-FU, was found to show limited cytotoxic potential in vitro and did not significantly enhance cell killing after X ray exposure.

Cell Survival↗
PubMed1982

Clearance of continuously infused 5-fluorouracil in adults having lung or gastrointestinal carcinoma with or without hepatic metastases.

The steady-state apparent total body clearances (TBC) of continuously infused 5-fluorouracil (5-FU) were determined in 16 adult male patients who were receiving combined 5-FU-radiation therapy. Seven patients (group A) had Stage III adenocarcinoma or epidermoid lung carcinomas; none had known metastases. Five patients had gastrointestinal carcinomas (group B), without known hepatic metastases. Four had gastrointestinal carcinomas with evidence of hepatic metastases (group C). TBCs were calculated from infusion rates and serum 5-FU concentration data. The means (standard errors) of the TBCs were: group A, 4.49 (0.53); group B, 6.51 (0.53); group C, 2.96 (0.91) L/kg/h. The difference among the means was found to be significant (p less than 0.002) by one-way ANOVA. Differences among the groups were then examined using 95 percent confidence intervals: group A was not different from group B or group C; however, groups B and C differed from each other. Patients with hepatic metastases have 5-FU TBCs about half that of those found in patients without hepatic involvement. Clinically, patients in group C attained the higher serum 5-FU concentrations known to be radiosensitizing more frequently than patients in the other two groups; differences in toxicity were not evident. This suggests that administration of an agent that can compete with 5-FU for hepatic metabolism to patients with rapid clearance might improve the therapeutic efficacy of 5-FU.

Adult↗
PubMed1981

Surgical adjuvant therapy in colon carcinoma: a human tumor spheroid model for evaluating radiation sensitizing agents.

HT-29 human colon tumor cells growing as spheroids have been evaluated as a model system for measuring the response of human colon tumor cell to antineoplastic agents. HT-29 cells have been capacity to form spheroids up to 1 mm or more in diameter when grown in spinner culture. The multicellular HT-29 spheroids develop hypoxic centers reflecting the cellular conditions found in human cancer treatment, i.e., nutritionally deficient hypoxic cells that are felt to be a significant source of both radiation and chemotherapy clinical treatment failures. Spheroids of increasing size were radiated and then dispersed into single cells for colony survival assay. Compared with irradiated single cell suspensions, the spheroid cells demonstrated a significant increase in radioresistance. Growing spheroids developed a complex radiation survival curve which was variable with respect to size of the spheroid. The drug 5-Fu was studied to examine in a preliminary fashion its interaction with these resistant cell fractions. In direct cytotoxicity assay, 5-fluorouracil (5-FU) exhibited both cytotoxic and cytostatic effects when the drug was present at a concentration greater than 0.4 microgram/ml. The interaction of 5-FU with x-rays in the HT-29 spheroids was complex and dependent on the type of assay employed (spheroid size versus clonogenicity). The effect of allopurinol, an agent that protects cells from 5-FU toxicity was examined. Allopurinol at a concentration of 100 microgram/ml was found to protect these human colonic carcinoma cells from the cytotoxic effects of 5-FU under conditions resembling those found in vivo. Overall, this HT-29 spheroid system appears to b an interesting model for studying a variety of drug/x-ray interactions in vitro and may prove capable of answering specific questions of preclinical and clinical relevance.

Allopurinol↗
PubMed1981

Improved liquid chromatographic assay for serum fluorouracil concentrations in the presence of ftorafur.

An improved liquid chromatographic assay for serum ftorafur and fluorouracil is shown to be routine, sensitive, and reproducible using 200 micro l of serum. Dilute ammonium acetate buffer at pH 10.2 is used for solubilization of the evaporated ethyl acetate extract for injection into the liquid chromatograph. A stability study indicated little or no in vitro formation of fluorouracil from ftorafur under the conditions described. Low serum fluorouracil levels were found after administration of therapeutic doses of ftorafur.

Chromatography, Liquid↗
PubMed1981

Irreparable DNA cross-links and mammalian cell lethality with bifunctional alkylating agents.

The appearance and removal of DNA cross-links in C3H10T1/2 cells has been investigated with closely related bifunctional alkylating agents having widely different kinetics of alkylating activity. Concentrations of nitrogen mustard, phosphoramide mustard and melphalan demonstrating equivalent levels of cell lethality indicate a correlation between the appearance of residual DNA cross-links, transformation and the loss of colony formation ability. Residual DNA cross-links appear to remain after repair is nearly complete by 24 h and consist of both the interstrand DNA and DNA-protein varieties. These adducts occur in the general population of cells despite the fact that these cells retain their DNA cross-link repair capabilities. Less than 100 interstrand DNA cross-links and a 10-fold greater number of DNA-protein cross-links are estimated to remain in the DNA after a 66% lethal dose of these compounds. Due to the obvious complications involving DNA replication in the presence of such lesions, residual DNA cross-links may possibly be associated with lethality in these cells. Current evidence demonstrating the formation of additional sites of alkylation such as irreparable phosphotriester adducts by several alkylating agents may suggest a role for a specific type of DNA damage in this process.

Alkylating Agents↗
PubMed1981

The structure of methylated xanthines in relation to their effects on DNA synthesis and cell lethality in nitrogen mustard-treated cells.

The variation in cellular response to alkylated xanthines possessing different side chains has been used to evaluate more fully the effect of caffeine on both survival and DNA synthesis in cells with DNA damage. A correlation is observed between the ability of these xanthines to reverse the inhibitory effects of nitrogen mustard damage on DNA synthesis and their ability to enhance nitrogen mustard lethality in human HT-29 cells. These findings are consistent with our theory that regulation of damaged replicon initiation protects against potentially lethal damage in the form of unrepaired DNA alkylations. Enhancement of nitrogen mustard lethality is observed to have a maximum limit, which can be reduced by highly toxic xanthine concentrations. The lethal effects of xanthines alone at higher concentrations are unrelated to the effects of caffeine specific to nitrogen mustard treated cells, and appear to be related to an immediate reduction in thymidine incorporation most likely caused by inhibition of other enzyme systems influencing DNA synthesis such as de novo and salvage pathways for purine biosynthesis.

Adenocarcinoma↗
PubMed1981

Mice, men, mustard and methylated xanthines: the potential role of caffeine and related drugs in the sensitization of human tumours to alkylating agents.

The relationships between DNA damage from UV radiation, alkylating drugs and the methylated xanthines (MX) have been studied in normal and malignant rodent and human cells. A comparison of the level of DNA excision repair (repair replication and unscheduled DNA synthesis) confirms that some forms of alkylating-agent damage (probably mono-filar DNA adducts) are less completely removed by both normal and malignant rodent cells than by their human counterparts, rendering rodent cells more susceptible to the toxic potential of unexcised lesions. The toxicity of alkylating agents can be increased by the presence of several MXs during the period of DNA replication which follows infliction of the damage. Human cells appear capable of excising more DNA damage, rendering them somewhat less susceptible to enhancement of cytotoxicity by MX. This resistance of human cells is only quantitative, however, since 2 human cancer cell lines (HeLa and HT-29) could be sensitized to a variety of alkylating agents by appropriate concentrations of MX. Trimethylxanthine (caffeine) and the 2 clinically useful dimethylxanthines (theophylline and theobromine) appeared equally effective in sensitizing cells. The sensitization was dependent upon a slightly cytotoxic concentration of the MX and a suitably prolonged period of post-damage MX exposure. Of these 3 classic MXs, only theobromine might be clinically useful. The levels required for alkylating-agent sensitization exceed the clinically tolerable level of theophylline, and probably approach the tolerance of man to caffeine. The most likely mechanism by which MX sensitization is achieved is reversal of the inhibition of DNA replicon initiation which follows the infliction of significant DNA damage. Through the selection of suitable clinically useful alkylating agents (those dependent on active cellular transport for cell penetration) and appropriate MX scheduling, an enhanced therapeutic ratio might be achieved, potentially increasing the clinical usefulness of these alkylating agents. MX would thus form a useful class of agents adjuvant to conventional anti-cancer drugs.

Alkylating Agents↗
PubMed1980

Effects of methylated xanthines on mammalian cells treated with bifunctional alkylating agents.

Caffeine has been previously reported to enhance the lethal potential of many DNA-damaging agents in rodent cells1-5. This effect has most commonly been ascribed to the binding of caffeine to single-stranded DNA6, and the resulting inhibition of post-replication repair7-10, which is associated with the synthesis of abnormally small nascent DNA fragments7, 11-13. However, certain aspects of this theory remain unclear:(1) why does the addition of caffeine to damaged cells elevate the level of DNA synthesis when it supposedly blocks post-replication repair10,14, and (2) as pointed out by Cleaver15, why does caffeine continue to exert its synergistic lethal effects until completion of the S phase16, 17, even though the size of newly synthesized DNA seems normal much earlier18-20? The present studies with nitrogen mustard (HN2) fail to demonstrate any effect of non-lethal concentrations of methylated xanthines (MXs) on removal of DNA damage or post-replication repair in conditions producing synergistic lethal effects. We demonstrate an influence by MXs on initiation of DNA synthesis in damaged replicons, and propose that this effect is primarily responsible for the synergistic lethal properties of these drugs.

Animals↗
PubMed1980

Infusional 5-fluorouracil and X-ray therapy for non-resectable esophageal cancer.

Six patients with unresectable carcinoma of the esophagus received a combined course of external radiation therapy (1000 rads in four fractions in four days commencing on day 2) combined with constant infusional 5-fluorouracil (20 mg/kg every 24 hours for five days beginning on day 1). This program was repeated every other week to give a total x-ray dose of 6000 rads. This regimen has been well-tolerated by the majority of the patients and resulted in a complete response rate within the x-ray treatment field of 83% (5/6). All patients who showed a demonstrable systemic response to 5-fluorouracil reached complete response. The median survival has not yet been reached at six months with post-treatment survivors alive and without disease (four patients) at one, six, nine, and 22 months. Our previous median survival by x-ray therapy alone was 4 1/2 months. Toxicity consists primarily of hematologic suppression at a subclinical level. Although the length of therapy is substantial (11 weeks), the program appears tolerable and is capable of inducing long-term remissions. The program is currently being studied for dose escalation because neither local nor systemic side effects of a dose-limiting nature have been observed at 20 mg/kg 5-FU.

Bone Marrow↗