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Biomedical subjects

G Morstyn

Publications and source records attributed to G Morstyn.

At least 91 records · Page 5Linked to original sources
PubMed1987

Carboplatin (CBDCA, JM-8) and VP-16-213 in previously untreated patients with small-cell lung cancer.

The efficacy and toxicity of carboplatin 100 mg/m2, administered intravenously (IV) daily X 3, and VP-16-213 120 mg/m2, IV daily X 3, administered every 28 days for six courses, was assessed in 94 (36 limited stage, 58 extensive stage) previously untreated patients with small-cell lung cancer. Mediastinal irradiation using 50 Gy in 25 fractions was given to all limited-stage patients with a complete (CR) or partial response (PR) after three chemotherapy courses. Cranial irradiation was administered to all patients with CR. Objective responses were seen in 77% (CR 40%, PR 37%) of patients with limited-stage and 58% (CR, 9%; PR, 49%) with extensive-stage disease. Median relapse-free survival for objective responders with limited stage was 14.6 months and 7.9 months for extensive-stage patients. Median relapse-free survival following CR was 15.4 months and 8.5 months for PR. Median survival was 15.3 months for limited-stage and 8.1 months for extensive-stage patients. The combination was well tolerated with mild nausea or less (World Health Organization [WHO] grade 0 or 1) in 62% of patients and minimal mucositis, renal, neurotoxicity, or ototoxicity. Neutropenia less than 1.0 X 10(9)/L (WHO grade 3 or 4) was seen in 63% of patients, with two deaths from infection while neutropenic. The combination of carboplatin and VP-16-213 is a new, active program with low toxicity when applied intensively in previously untreated patients with small-cell lung cancer.

Adult↗
PubMed1987

Photoradiation therapy causing selective tumor kill in a rat glioma model.

We evaluated the effect of photoradiation therapy using the photosensitizer, hematoporphyrin derivative (HpD), and the argon-pumped rhodamine dye laser tuned to 630 nm in the rat C6 glioma model. Animal models of cerebral glioma were established by implanting 10(6) C6 glioma cells in adult Wistar rats, and craniotomies were performed on normal and tumor-bearing animals. HpD in doses of up to 80 mg/kg followed by craniotomy resulted in no damage to the normal brain, and laser light at doses of up to 1200 joules/cm2 without the prior administration of HpD produced no significant damage if the craniotomy site was irrigated with normal saline to prevent a temperature rise. Photoradiation caused no brain necrosis in non-tumor bearing animals if less than 20 mg of HpD per kg and 200 joules of red light per cm2 were used. At higher doses of HpD and light, cerebral necrosis did occur. The depth of necrosis depended on the dose of both HpD and light. Treatment with 40 mg of HpD per kg and 400 joules of light per cm2 resulted in cerebral necrosis in 50% of the treated animals. The mean depth of brain necrosis was 1.3 mm. Selective kill of a cerebral glioma with sparing of the normal brain was achieved with photoradiation therapy at doses of HpD of less than 20 mg/kg and light doses of less than 200 joules/cm2. At these doses, the mean depth of tumor kill was 4.5 mm. In 2 of 10 animals, the depth of tumor destruction was more than 6 mm.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Adjuvant high-dose photoradiation therapy in the treatment of cerebral glioma: a phase 1-2 study.

A Phase 1-2 study of high-dose photoradiation therapy was performed in 23 patients with cerebral tumors. Twenty-two patients had high-grade gliomas (13 glioblastomas, six recurrent glioblastomas, two anaplastic astrocytomas, and one recurrent anaplastic astrocytoma) and one had a right frontal metastasis from a carcinoma of the lung. Hematoporphyrin derivative was administered to these patients in a dose of 5 mg/kg and, 24 hours later, they all underwent a craniotomy with radical excision of the tumor. The tumor bed was then irradiated with 630 nm of laser light from either an argon dye laser or a gold metal vapor laser for between 43 and 94 minutes, receiving total doses of 70 to 120 J/sq cm (six cases) or 120 to 230 J/sq cm (17 cases). The temperature of the tumor bed was kept below 37 degrees C by irrigation. Fifteen patients who developed new tumors underwent postoperative radiotherapy (45 Gy in 20 divided doses). There was no evidence of increased cerebral edema and no other toxicity from the therapy. All patients were discharged from the hospital within 18 days of surgery. Four of seven patients with gliomas have suffered a further recurrence at 12 to 16 weeks, and two of 15 patients with primarily treated gliomas experienced recurrence at 3 and 13 months following therapy. Fifteen patients have had no recurrence of their tumor and are alive and well at a median follow-up period of 7 months (range 1 to 16 months). It is concluded that photoradiation therapy using 5 mg/kg of hematoporphyrin derivative and 630 nm light at doses of up to 230 J/sq cm can be used as an adjuvant to surgery and radiotherapy with no additional complications.

Adolescent↗
PubMed1986

Immunohistochemical identification of proliferating cells in organ culture using bromodeoxyuridine and a monoclonal antibody.

The ability to measure cell proliferation is important in the study of cancer biology. The usual technique for quantitating proliferating cells in tissue explant and organ culture by detection of [3H]-thymidine incorporation into DNA by autoradiography is tedious and time-consuming. We have developed a technique for identification and quantitation of bromodeoxyuridine (an analogue of thymidine) in cultured tissue explants. Fetal mouse colon explants were exposed in vitro to bromodeoxyuridine (BUdR) or [3H]-thymidine for 3 to 72 hr and then for various periods to unlabeled thymidine. The tissues were stained with a monoclonal anti-bromodeoxyuridine antibody and in parallel [3H]-thymidine incorporation was detected by autoradiography. Incorporation of BUdR was measured by quantitating the amount of pigment deposited over nuclei after immunohistochemical staining, using an optical data digitizer. It was found that both techniques identified proliferating cells. Dividing cells were present both in crypts and in the surrounding stroma in Day 14 fetal mouse colon cultures. The immunohistochemical technique was more rapid and less cumbersome than autoradiography.

Animals↗
PubMed1986

Improved survival in esophageal cancer in the period 1978 to 1983.

The outcome of therapy of adenocarcinomas and squamous-cell carcinomas of the esophagus is so poor that the results of new approaches to therapy, such as the addition of radiotherapy or chemotherapy, are often compared with those achieved in historical controls. To determine the validity of this approach in cancers with a poor outcome, the results of therapy were analyzed at our institution from Jan 11, 1978 to Aug 9, 1981 (77 patients) and compared with the results achieved in the period from Aug 14, 1981 to Feb 19, 1984 (77 patients). The patients were evenly matched for prognostic factors. It was found that the median survival of the first group of patients (4 months) was significantly less (P less than .01) than that of the recently treated group (10 months). This was due to the better median survival of patients treated surgically from 4 months in the early group to 29 months at present (P less than .01). There was no change in the survival of the other patients. The major improvement in the outcome of surgery was due to the reduction of the perioperative mortality rate to less than 5%. There was no detectable change in patient selection for surgery. The results indicate that even in tumors with a very poor outcome, such as esophageal cancer, large changes in results can occur without a specific change in therapy, and that historical controls may be misleading.

Adenocarcinoma↗
PubMed1986

Development of a xenograft glioma model in mouse brain.

Xenograft intracerebral glioma models have been developed in normal mice by growing the rat C6 glioma in either adult or neonatal mouse brains. Using this tumor line it was possible to grow discrete intracerebral gliomas in either CBA or AKR adult mice or neonatal mice. The size of the tumor mass and length of survival was directly related to the number of tumor cells injected and the time after implantation. To obtain localized intracranial tumor growth cells were suspended in a 1% agarose solution before implantation. Following injection of 10(6) cells into the frontal lobe of adult CBA or AKR mice, discrete tumor masses greater than 4 mm in diameter were obtained in 90% of animals at 14 days, and the largest tumors in adult mice occurred between 21 and 28 days after implantation. The tumor size following implantation of 10(6) cells was significantly greater than with 10(5) cells at 7 days (P less than 0.05) and at 14 and 21 days (P less than 0.01). Less than 60% of mice of BALB/c, RIII, or C57 black strains developed tumors greater than 4 mm diameter at 14 days after intracerebral injection of 10(6) C6 cells. Using neonatal mice it was found that when 10(5) cells were injected intracranially tumors greater than 4 mm in diameter developed in 14 of 15 animals within 2 weeks (CBA mice). Similar results were seen in the RIII, AKR, C57 black, and BALB/c strains. Longer growth periods resulted in larger tumors, up to 8 mm in diameter (6 of 10 animals at 20 days). The tumors in the neonatal animals were not as discrete as in the adult mice, and tumor often spread to the meninges and into the lateral ventricles. The tumor harvested from the brain had a cloning efficiency of 1.2 +/- 0.4% (SD). A panel of monoclonal antibodies was raised to the C6 glioma, and this was used to define clearly the margins of the tumor within the brain. The xenograft mouse models should prove useful for the study of the therapy of gliomas.

Animals↗
PubMed1985

Hand-mirror variant of acute lymphoblastic leukemia. Evidence for early T-cell lineage in two cases by evaluation with monoclonal antibodies.

Lymphoid cells from two patients with hand-mirror variant of acute lymphoblastic leukemia (ALL) were studied with various monoclonal antibodies in attempts to determine their derivation and differentiation. The predominant feature of the malignant bone marrow cells was strong reactivity with antibody 3A1, which stains the majority of normal T-cells and is apparently present on all T-ALL cells. In addition, a less intense binding was observed with antibody 4F2, which reacts with activated or rapidly dividing cells, and antibody 10.2, which reacts with all thymocytes and most peripheral T-cells. Most other antibodies with a wide variety of specificities were not reactive or, in the case of a few anti-T-cell antibodies showed, by fluorescence-activated cell sorter analysis only weak staining on some cells. Sequential bone marrow studies in one patient, before and during treatment with chemotherapy, revealed a reduction of 3A1-positive cells, concordant with a decrease of malignant cells in the marrow. When involved lymph nodes, peripheral blood, or marrow were studied, similar reactivity patterns were found in all locations. The data obtained suggest that in both patients with hand-mirror variant of ALL, the malignant lymphoid cells were immature cells of early T-lymphocyte lineage. The relation of phenotype by monoclonal antibody analysis to hand-mirror morphologic type and biologic function is discussed.

Adolescent↗
PubMed1985

Uptake and retention of hematoporphyrin derivative in an in vivo/in vitro model of cerebral glioma.

Photoirradiation treatment depends on exposing tumors to a photosensitizer and light to achieve selective tumor kill. We evaluated the kinetics of uptake of a photosensitizer, hematoporphyrin derivative (HpD), in an animal model of cerebral glioma to ascertain the optimal time for photoirradiation therapy. Animal models of cerebral glioma were established by implanting cells from the rat C6 glioma cell line into rat brains or as xenografts in adult mouse brains. C6 cells (10(7] injected into the frontal lobe of adult Wistar rats produced intracranial tumors greater than 5 mm in diameter in 90% of the animals at 21 days. Tumors greater than 4 mm in diameter developed in adult mouse brains within 14 days after 10(6) cells were implanted into the frontal lobe. These two tumor models were used to investigate the localization of HpD. After HpD administration, its presence was detected in fresh, unfixed specimens by fluorescence emission after excitation with an ultraviolet lamp. Fluorescence was determined quantitatively by an image analysis method using an optical data digitometer. The fluorescence, which was highly localized selectively to the intracerebral tumor, was just detectable 5 minutes after an intravenous injection of HpD. Patchy, bright fluorescence was evident 4 hours after injection, and the tumor was uniformly fluorescent after 6 hours. A minimal dose of 0.5 mg of HpD per kg of body weight was necessary to produce detectable fluorescence, and the dose of HpD necessary to produce detectable fluorescence was 4 mg/kg of body weight. The intracarotid route of administration was unsatisfactory because seizures were induced, and intrathecal injection did not produce significant fluorescence in the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

In vivo incorporation of bromodeoxyuridine into proliferating cells in the marrow and its effects on granulocyte-macrophage progenitor cells.

Bromodeoxyuridine (BUdR), a potential radiosensitizing drug, was given by intravenous infusion at 650-1000 mg/m2/day for up to 12 days. In vivo incorporation into human bone marrow was assayed by differential chromatid staining as well as by comparison of in vitro radiation survival curves of granulocyte-macrophage progenitor cells scored at both day 7 and day 14. Although a difference was found in the radiation survival of control (untreated) day-7 progenitor cells (Do = 1.39 Gy) and day-14 progenitor cells (Do = 0.89 Gy), a similar degree of in vitro radiosensitization was found for BUdR-treated bone marrow progenitor cells scored at day 7 and day 14. The culture technique provided a bioassay for the in vivo action of BUdR. BUdR treatment produced transient moderate myelosuppression that probably resulted from BUdR incorporation into normal marrow cells.

Bone Marrow↗
PubMed1985

Specific killing of human melanoma cells by 125I-labeled 9.2.27 monoclonal antibody.

The anti-melanoma antibody 9.2.27 localizes to melanoma cells when administered i.v. to melanoma patients, but high doses of this antibody alone have no specific cytotoxic effect in vivo. To determine whether radiolabeled antibodies would exhibit specific antimelanoma cytotoxicity in vitro, cell survival curves were established for NCl-N892 human melanoma cells treated with 125I-labeled 9.2.27 monoclonal antibody. The binding capacity per cell was 5 X 10(5) molecules of 9.2.27 immunoglobulin G, and the association constant of binding was 10(10) M-1. Antibody preparations with specific radioactivities of 9-80 microCi/micrograms were used. Colony-forming ability after in vitro exposure to 125I-9.2.27 was determined by a 1-h antibody incubation at saturating concentrations, washing, and cell freezing for various exposure durations. Colony survival was dose dependent, varying with the radioactivity per cell and the exposure time. The survival curves demonstrated no shoulder effect and had a 37% incremental survival dose of 0.5-0.9 X 10(5) decays/cell. Selective killing of melanoma cells was demonstrated in experiments where NCl-N417 lung cancer cells were mixed with the melanoma cells prior to antibody treatment. The NCl-N417 cells did not express the melanoma-associated antigen, were more sensitive to conventional external irradiation than were the melanoma cells, and could easily be distinguished from them by different growth morphology. In spite of a growth advantage for the melanoma cells in the clonogenic assay, the antigen-negative lung cancer cells selectively survived the treatment and were the only surviving cells after 15 days of exposure.

Antibodies, Monoclonal↗
PubMed1985

Uptake of hematoporphyrin derivative by normal and malignant cells: effect of serum, pH, temperature, and cell size.

Normal and malignant cells were incubated with hematoporphyrin derivative (HPD) and their uptake and retention of HPD were analyzed by flow cytometry. In standard growth medium the amount of HPD taken up by cells was proportional to the added HPD concentration and reached a plateau level after 5-6 h of incubation. The uptake occurred in two steps; within seconds a large amount of HPD became loosely bound to the cells, presumably the outer membrane. This was followed by a slower uptake of HPD into the cytoplasm. The loosely bound portion could be washed from the cells by medium containing either fetal calf serum or serum albumin. At low temperatures the uptake into the cytoplasm was strongly reduced. A major determinant of HPD uptake was the concentration of serum in the medium. At any particular concentration of HPD below 200 mg/liter, increasing concentrations of fetal calf serum or bovine serum albumin resulted in a reduction in the amount of HPD taken up by cells. A further factor affecting uptake was the pH of the medium. At low pH (pH 6) the rate of HPD incorporation was much higher than at pH 7.4. Under identical conditions of incubation, HPD uptake was proportional to cell size as estimated using the low angle light scatter signal in the flow cytometer. Our data suggest that acidic pH, differences in extracellular serum concentrations of malignant tumor tissue, as well as the increased size of tumor cells may play an important role in the selective uptake of HPD by malignant tumors.

Animals↗
PubMed1984

Small cell lung cancer 1973-1983: early progress and recent obstacles.

The recognition that the vast majority of patients with small cell lung cancer have distant metastatic disease at the time of diagnosis led to the use of systemic chemotherapy and consequent major improvements in survival in the early to mid-1970's. In the past five years, however, the pace of therapeutic advances has slowed. Recently evaluated treatment strategies, including more intensive induction chemotherapy, "late intensive" therapy of responding patients, alternation of chemotherapeutic regimens, integration of chest irradiation with drug therapy, large field irradiation, and reappraisal of the value of surgical resection, are discussed in this review. Advances in understanding of the cell biology of small cell lung cancer which may eventually lead to new forms of treatment are summarized.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

The use of halogenated thymidine analogs as clinical radiosensitizers: rationale, current status, and future prospects: non-hypoxic cell sensitizers.

The halogenated pyrimidine analogs, bromodeoxyuridine (BUdR) and iododeoxyuridine (IUdR) have been recognized as potential clinical radiosensitizers for over two decades. In vivo and in vitro experimental studies document that radiosensitization is directly dependent on the amount of thymidine replacement in DNA by these analogs. Early clinical studies in Japan using selective intra-arterial infusions of BUdR and conventional fractionated radiation suggested improved survival in patients with primary brain tumors, although there were significant catheter-related complications. Based on recent in vivo and clinical pharmacology studies on continuous intravenous infusions of these drugs, clinical trials are underway evaluating the potential of radiosensitization in high grade gliomas and other poorly radioresponsive tumors using the technically safer intravenous route of administration. In this paper, we review the basic strategy for the use of these analogs, the ongoing clinical trials and the potential areas for future experimental and clinical studies.

Animals↗
PubMed1984

131-iodine conjugated antibody cell kill enhanced by bromodeoxyuridine.

131I-conjugated monoclonal and polyclonal antibodies are being administered in vivo to kill human tumor cells. Although these conjugates deliver relatively large doses of radiation to tumors (10 to 50 Gy), the rate of dose delivery is low (0.05 to 0.2 Gy/hour). Radiation delivered at low dose rates kills fewer cells that exhibit large shoulders on radiation survival curves than radiation delivered at high dose rates. To determine whether the cell kill produced by low dose rate radiation is enhanced by a radiation sensitizer (bromodeoxyuridine, BUdR) we studied the cell kill produced by an 131I-conjugated polyclonal antibody against Chinese hamster V79 cells. V79 cells were labeled with 131I-conjugated antibody (10-20 microCi/micrograms) and unconjugated antibody, and frozen for up to 30 days in liquid nitrogen. The surviving fraction of cells was measured at intervals of 5 to 10 days. Cells not containing BUdR were also studied. The 131I-conjugated antibody produced up to 40% cell kill and BUdR increased the fraction of cells killed to 75%. Our studies demonstrate that cells frozen at -196 degrees C are useful for the investigation of the cell kill produced by isotopes that deliver radiation at low dose rates and that the cell kill caused by 131I-conjugated antibodies can be enhanced by BUdR.

Animals↗
PubMed1984

Identification of bromodeoxyuridine in malignant and normal cells following therapy: relationship to complications.

During a clinical Phase I study of bromodeoxyuridine (BUdR) as a radiation sensitizer we identified the normal and malignant cells that incorporated the BUdR. BUdR was infused for up to 14 days and the in vivo incorporation of BUdR into DNA was assessed using an immunohistochemical technique and a monoclonal antibody directed against BUdR. BUdR was identified in 50% of breast cancer cells and 10% of cells in a malignant melanoma. BUdR was also found in the basal layer of the normal epidermis and in 50% of cells in the marrow. The incorporation of BUdR into cells in the epidermis and marrow may produce the phototoxicity and myelosuppression observed in patients treated with BUdR. Sequential biopsies from a breast cancer taken prior to and following radiotherapy suggested that cells that incorporated BUdR may have been selectively killed by the radiation. The immunohistochemical technique used to identify BUdR appeared to be useful for studies of in vivo and in vitro cell proliferation.

Bone Marrow↗
PubMed1984

Differing sensitivity to fluorescent light in Chinese hamster cells containing equally incorporated quantities of BUdR versus IUdR.

Chinese hamster V79 cells that had incorporated approximately equal levels of either BUdR or IUdR into their DNA were found to be equal sensitizers to X rays. However, BUdR-substituted cells were much more sensitive to fluorescent light than IUdR-substituted cells, both on a cell survival basis and by the initial number of single strand DNA breaks induced. Since a major toxicity to the use of BUdR clinically has been light-induced skin rash, these data indicate that the use of IUdR clinically might cause less untoward toxicity but yet provide the same radiosensitization as BUdR.

Animals↗
PubMed1984

Continuous intravenous infusions of bromodeoxyuridine as a clinical radiosensitizer.

Twelve patients were treated with continuous intravenous (24-hour) infusions of bromodeoxyuridine (BUdR) at 650 or 1,000 mg/m2/d for up to two weeks. Myelosuppression, especially thrombocytopenia, was the major systemic toxicity and limited the infusion period to nine to 14 days. However, bone marrow recovery occurred within seven to ten days, allowing for a second infusion in most patients. Local toxicity (within the radiation field) was minimal, with the exception of one of four patients, who underwent abdominal irradiation. Pharmacology studies revealed a steady-state arterial plasma level of 6 X 10(-7) mol/L and 1 X 10(-6) mol/L during infusion of 650 and 1,000 mg/m2/d, respectively. In vivo BUdR uptake into normal bone marrow was evaluated in two patients by comparison of preinfusion and postinfusion in vitro radiation survival curves of marrow CFUc with enhancement ratios (D0-pre/D0-post) of 1.8 (with 650 mg/m2/d) and 2.5 (with 1,000 mg/m2/d). In vivo BUdR incorporation into normal skin and tumor cells using an anti-BUdR monoclonal antibody and immunohistochemistry was demonstrated in biopsies from three patients revealing substantially less cellular incorporation into normal skin (less than 10%) compared with tumor (up to 50% to 70%). We conclude that local and systemic toxicity of continuous infusion of BUdR at 1,000 mg/m2/d for approximately two weeks is tolerable. The observed normal tissue toxicity is comparable with our previous clinical experience with intermittent (12 hours every day for two weeks) infusions of BUdR. Theoretically, a constant infusion should allow for greater incorporation of BUdR into cycling tumor cells and thus, for further enhancement of radiosensitization.

Bone Marrow↗