Search PubMed⌕ Search

Biomedical subjects

H A Fine

Publications and source records attributed to H A Fine.

At least 37 records · Page 2Linked to original sources
PubMed1996

Viral vector transduction of the human deoxycytidine kinase cDNA sensitizes glioma cells to the cytotoxic effects of cytosine arabinoside in vitro and in vivo.

Cytosine arabinoside (ara-C) is a cytidine analog that incorporates into replicating DNA and induces lethal DNA strand breaks. Although ara-C is a potent antitumor agent for hematologic malignancies, it has only minimal activity against most solid tumors. The rate-limiting step in intracellular ara-C activation is phosphorylation of the prodrug by deoxycytidine kinase (dCK). The present results demonstrate that both retroviral and adenoviral vector-mediated transduction of the dCK cDNA results in marked sensitization of glioma cells lines to the cytotoxic effects of ara-C in vitro. We also demonstrate that ara-C treatment of established intradermal and intracerebral gliomas transduced with dCK results in significant antitumor effects in vivo. These data suggest that viral vector transduction of the dCK gene followed by treatment with ara-C represents a new chemosensitization strategy for cancer gene therapy.

Adenoviridae↗
PubMed1996

Gene therapy for malignant gliomas using replication incompetent retroviral and adenoviral vectors encoding the cytochrome P450 2B1 gene together with cyclophosphamide.

Cyclophosphamide is an inactive prodrug which is converted by hepatic cytochrome P450 2B1 to cytotoxic metabolites which produce interstrand DNA cross-linking in a cell cycle-independent fashion. The limited ability of these metabolites to cross the blood-brain barrier contributes to the poor activity of cyclophosphamide against brain tumors. In this study we demonstrate that replication deficient retroviral and adenoviral vector-mediated gene transfer of cytochrome P450 2B1 into 9L glioma cells significantly increases the sensitivity of these tumor cells to cyclophosphamide in vitro, and prolongs the survival of animals bearing intracerebral 9L tumors treated with cyclophosphamide in vivo. Attempts to improve the effectiveness of retrovirally mediated transduction of the P450 2B1 gene by increasing the concentration of cyclophosphamide delivered to the tumors using intracarotid and intratumoral injections did not prolong animal survival, although survival was increased when a second treatment with P450-expressing retroviral vectors and cyclophosphamide was administered. These results suggest that in situ transduction of tumor cells with the P450 2B1 gene using retroviral and adenoviral vectors increases their sensitivity to cyclophosphamide and may have a potential role in the therapy of malignant gliomas.

Adenoviridae↗
PubMed1995

Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases.

BACKGROUND: The spread of systemic cancer to the brain is a common complication for cancer patients. Conventional radiotherapy offers modest palliation, and surgery is helpful only for the patient with a single metastasis in an accessible location. Stereotactic radiosurgery, a technique that permits the precise delivery of a high dose of radiation to a small intracranial target while sparing the surrounding normal brain, has been used as an alternative treatment for brain metastases. PURPOSE: Our medical center's 7-year experience with radiosurgery for metastases was reviewed to establish the effectiveness of the treatment and to understand the prognoses in patients so treated. METHODS: Retrospective analysis of hospital records, from 248 consecutive patients (421 lesions) that were treated with radiosurgery between May 1986 and May 1993, was performed. Patients were only excluded for a Karnofsky performance score of less than 70, evidence of acute neurologic deterioration, or tumor diameter more than 4 cm. Median follow-up was 26.2 months. Seventy-six percent of patients had recurrent disease, 69% had evidence of systemic disease, 69% had a single metastasis. Treatment was performed using a 6-MeV linear accelerator. The median tumor volume was 3 cm3. The median treatment dose was 1500 cGy. Whole brain radiotherapy was given to all newly diagnosed patients. Patients were followed by neurological examination and neuroimaging at regular intervals. Local control of disease was defined as a lack of progression of solid-contrast enhancement on computed tomography scan or magnetic resonance imaging. RESULTS: Median overall survival from radiosurgery was 9.4 months. The absence of active systemic disease, younger than 60 years of age, two or fewer lesions, and female sex were significantly associated with increased survival (two-sided P < .05). Actuarial local control rates were approximately 85% at 1 year and 65% at 2 years. Factors associated with a significantly decreased local control rate were location below the tentorium, recurrent tumor, and larger tumor volume (two-sided P < .05). Radioresponsive and radioresistant tumor types had similar control rates. The median drop in Karnofsky performance score at 1 year was 10%. CONCLUSIONS: The results of this retrospective analysis show that radiosurgery is an effective, minimally invasive outpatient treatment option for small intracranial metastases. Results of this study also indicate that radiosurgery not only provides local control rates equivalent to those from surgical series but is also effective in treating patients with surgically inaccessible lesions, with multiple lesions, or with tumor types that are resistant to conventional treatment.

Adolescent↗
PubMed1995

Monocyte chemoattractant protein-1 (MCP-1) gene transduction: an effective tumor vaccine strategy for non-intracranial tumors.

Recently, there has been renewed interest in the concept of tumor vaccines using genetically engineered tumor cells expressing a variety of cytokines to increase their immunogenicity. Human MCP-1 (JE) is a potent chemoattractant and activator of monocytes and T lymphocytes and thus a good candidate gene for a tumor vaccine. We therefore evaluated the efficacy of vaccines consisting of irradiated tumor cells transduced with the murine MCP-1 gene in the syngeneic 9L gliosarcoma brain tumor model. 9L cell lines stably expressing murine MCP-1 (9L-JE) and control cell lines expressing neomycin 3' phosphotransferase (9L-Neo) were generated by infection with a Moloney murine leukemia retroviral vector. Fisher 344 rats were immunized with intradermal injections of 5 x 10(5) or 2 x 10(6) irradiated (5000 cGy) 9L-JE, 9L-Neo, and wild-type 9L (9L-WT) cells. Two weeks later immunized and non-immunized animals were challenged with various doses of intradermal (5 x 10(6)-5 x 10(7) or intracerebral (2 x 10(4)-5 x 10(5) 9L-WT cells. Intradermal tumors grew in all non-immunized animals. No tumors grew in animals immunized with irradiated 9L-JE or 9L-Neo cells and challenged with inocula of fewer than 5 x 10(5) 9L-WT cells. With higher inocula up to 10(7) cells, tumors appeared in all the animals, but subsequently regressed in the immunized animals. Tumors in animals immunized with 9L-JE were always smaller than tumors in the other groups. In addition, only the 9L-JE vaccine protected against tumor inocula of 5 x 10(7) cells. Thus vaccination with MCP-1-expressing cells was able to protect animals against at least a 100-fold larger number of challenge tumor cells than vaccination with control cells. In contrast to studies with intradermal tumors, immunization with 9L-JE and 9L-Neo produced only minimal protection against intracerebral tumors. There was no significant difference between the 9L-JE and 9L-Neo vaccines in intracerebral challenge. This study suggests that tumor vaccines expressing cytokine genes such as MCP-1 can increase the antitumor response. However, the protective effect of these vaccines appears to be largely limited to intradermal tumors rather than intracerebral tumors.

Animals↗
PubMed1995

Breast cancer selective gene expression and therapy mediated by recombinant adenoviruses containing the DF3/MUC1 promoter.

The high molecular weight mucin-like glycoprotein, DF3 (MUC1), is overexpressed in the majority of human breast cancers. Here we demonstrate that replication defective recombinant adenoviral vectors, containing the DF3 promoter (bp -725 to +31), can be used to express beta-galactosidase (Ad.DF3-betagal) and the herpes simplex virus thymidine kinase (HSV-tk) gene (Ad.Df3-tk) in DF3 positive breast carcinoma cell lines. In vivo experiments using breast tumor implants in nude mice injected with Ad.DF3-betagal demonstrated that expression of the beta-galactosidase gene is limited to DF3-positive breast cancer xenografts. Moreover, in an intraperitoneal breast cancer metastases model, we show that i.p. injection of Ad.DF3-tk followed by GCV treatment results in inhibition of tumor growth. These results demonstrate that utilization of the DF3 promoter in an adenoviral vector can confer selective expression of heterologous genes in breast cancer cells in vitro and in vivo.

Adenoviruses, Human↗
PubMed1995

Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme.

The purpose of this study was to compare the efficacy of stereotactic radiosurgery (SRS) and brachytherapy in the treatment of recurrent glioblastoma multiforme (GBM). The patients had either progressive GBM or pathologically proven GBM at recurrence after previous treatment for a lower grade astrocytoma. Thirty-two patients were treated with interstitial brachytherapy, and 86 received treatment with stereotactic radiosurgery (SRS). The patient characteristics were similar in the two groups. Those patients treated with SRS had a median tumor volume of 10.1 cm3 and received a median peripheral tumor dose of 13 Gy. Patients treated with brachytherapy had a median tumor volume of 29 cm3. Median dose to the periphery of the tumor volume was 50 Gy delivered at a median dose rate of 43 cGy/hour. Twenty-one patients (24%) treated with SRS were alive, with a median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with SRS was 10.2 months, with survivals of 12 and 24 months being 45 and 19%, respectively. A younger age and a smaller tumor volume were predictive of better outcome. The tumor dose, the interval from initial diagnosis, and the need for reoperation were not predictive of outcome after SRS. Five patients (16%) treated with brachytherapy were alive, with a median follow-up of 43.3 months. The median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals of 12 and 24 months were 44 and 17%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Novel biologic therapies for malignant gliomas. Antiangiogenesis, immunotherapy, and gene therapy.

Despite 20 years of clinical investigation of new surgical, radiotherapeutic, and chemotherapeutic approaches to the treatment of malignant gliomas, the prognosis for these patients remains dismal. New and innovative strategies are clearly required. The explosion of knowledge in molecular biology and our ever-increasing understanding of the molecular pathogenesis of neoplasia has opened up a number of new approaches to the treatment of brain tumors. The development and refinement of these strategies will require an unprecedented degree of collaboration and communication between the basic scientist, pharmaceutical/biotechnology companies, and clinical investigators. Most of all, the ability to identify novel and effective strategies will ultimately depend on the private clinician and his or her willingness to encourage patients with these tumors to participate in well-designed clinical trials that will test these novel strategies. With support from clinicians, and the close collaboration of investigators, it is hopeful that the next 20 years will bring significantly greater advances in the treatment of malignant gliomas than has ever been seen before.

Adult↗
PubMed1995

High-grade astrocytomas.

Despite intense research, progress in the treatment of patients with HGA has remained slow. New therapeutic strategies are emerging, however, based on technologic advances in surgery and radiotherapy, improved understanding of the molecular, cellular, and immunobiology of astrocytomas, and advances in gene therapy, It is likely that these new strategies will result in significant progress in the treatment of HGA in the next decade.

Adult↗
PubMed1994

Enhancer sequences of the DF3 gene regulate expression of the herpes simplex virus thymidine kinase gene and confer sensitivity of human breast cancer cells to ganciclovir.

A potentially novel therapeutic strategy for breast cancer treatment involves sensitization of tumor cells to chemotherapy through gene transfer. Clinical application of this approach, however, may be limited by the lack of target cell specificity of currently available gene delivery techniques. Development of vectors with tumor-selective gene expression could overcome this problem. The DF3/MUC1 gene encodes a high molecular weight mucin-like glycoprotein which is overexpressed at the transcriptional level in the majority of human breast cancers. To develop a breast tumor-selective enhancer, we cloned the upstream region of the DF3 gene and have identified a 114-base pair enhancer region that can modulate transcription from heterologous promoters. The present studies demonstrate that the DF3 enhancer sequences can direct selective gene expression in DF3-positive breast carcinoma cells. DF3-positive breast carcinoma cell lines transfected with herpes simplex virus thymidine kinase gene expression cassettes modified by the DF3 enhancer were markedly more sensitive to killing by ganciclovir than were the same cells transfected with the expression cassettes lacking the DF3 enhancer. DF3-negative cell lines transfected with the DF3 enhancer constructs, however, were no more sensitive to ganciclovir than were cells treated with the unmodified expression plasmids. Consistent with an innocent bystander effect, nontransfected human breast carcinoma cells were susceptible in a cell density-dependent manner to ganciclovir-induced cell killing when adjacent to transfected cells. The results also demonstrate that the DF3 enhancer sequences can be effectively incorporated into a retroviral vector to mediate selective gene expression following retroviral infection. These findings suggest that the DF3 promoter/enhancer may be useful for incorporation into vectors designed for gene therapy of breast cancer.

Base Sequence↗
PubMed1994

Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas.

BACKGROUND: Despite optimal therapy with surgery and radiotherapy, the prognosis of patients with glioblastomas remains poor. Stereotactic brachytherapy involves the accurate placement of radioactive isotopes within brain tumors, significantly increasing the dose of radiation that can be delivered to the tumor bed without substantial risk to surrounding normal tissue, potentially improving local tumor control and patient survival. METHODS: Between February 1987 and July 1993, the authors treated 56 patients with glioblastomas with stereotactic brachytherapy as part of their initial therapy. Patients underwent surgery, limited field external beam radiotherapy, and brachytherapy with temporary high-activity iodine 125 sources, giving an additional 50 Gy to the tumor bed. RESULTS: Median survival for patients undergoing brachytherapy was 18 months compared with 11 months for a matched brachytherapy control group with similar clinical and radiologic features (P < 0.0007). Survival rates at 1, 2, and 3 years after diagnosis of 83%, 34%, and 27%, respectively, for patients receiving brachytherapy were significantly increased compared with survival rates of 40%, 12.5%, and 9%, respectively, for control subjects. Thirty-six patients (64%) underwent reoperation for symptomatic radiation necrosis from 3 to 42 months (median, 11 months) after brachytherapy. The median survival of patients undergoing reoperation was 22 months compared with 13 months for those who did not have further surgery (P < 0.02). Thirty-five percent of patients relapsed locally within the brachytherapy target volume, whereas 65% had marginal or distant relapses. CONCLUSIONS: Brachytherapy may improve local tumor control and prolong survival when used in the initial treatment of selected patients with glioblastomas.

Adolescent↗
PubMed1994

The basis for current treatment recommendations for malignant gliomas.

Although primary brain tumors represent an important cause of cancer related mortality in the United States, advances in the treatment of these tumors has been slow and has generally lagged behind that of most systemic tumors. One of the major reasons for this is the paucity of well conducted, prospective radiation and chemotherapy trials. For the brain tumor trials that have been conducted, small patient numbers, heterogeneous patient populations, and non-uniformity of response criteria, have made the current clinical data base difficult to interpret. Data from several prospective, multi-institutional randomized trials have defined a role for radiation therapy in the treatment of malignant gliomas and on-going trials will help define refinements in technique. Although there does appear to be a place for the use of chemotherapy in the treatment of a subgroup of patients with malignant gliomas, its role for the majority of patients remains unclear. Only through better understanding of the biology of these tumors, more effective therapies, and the implementation of better clinical trial design can we hope to make significant progress in the treatment of malignant gliomas.

Antineoplastic Agents↗
PubMed1993

Primary central nervous system lymphoma.

OBJECTIVE: To compare the pathogenesis, clinical presentation, therapy, and prognosis of primary central nervous system lymphoma in immunocompetent persons with these characteristics of the disease in patients with AIDS. DATA SOURCES AND EXTRACTION: All English-language papers published between 1980 and 1992 dealing with either lymphoma and the central nervous system or AIDS were reviewed. Patient characteristics, clinical presentation, histologic findings, and treatment and survival data were extracted from each case report and review. DATA SYNTHESIS: Data were available on 792 patients (from 40 reported series) with non-AIDS-associated primary central nervous system lymphoma and 315 patients (from 32 series) with AIDS-associated primary central nervous system lymphoma. Patients with AIDS initially consulted a physician more often when they had global neurologic symptoms compared with patients without AIDS, with more than 50% of the lesions on computed tomographic (CT) scans in patients with AIDS being ring-enhancing and multifocal, a pattern rarely described in immunocompetent patients. The overall survival of the patients without AIDS was 18.9 months compared with 2.6 months for patients with AIDS, with substantial differences remaining even for subgroups of patients similarly treated with radiation and chemotherapy. CONCLUSION: Primary central nervous system lymphoma is probably a substantially different disease in persons with and without AIDS with regard to patient characteristics, clinical and radiographic presentation, and prognosis. Recent advances in the treatment of this disease in patients without AIDS have not largely affected patients with AIDS. Substantial improvements in survival in these patients await advances in controlling their human immunodeficiency virus-associated disease.

Central Nervous System Neoplasms↗
PubMed1993

Early response gene induction following DNA damage in astrocytoma cell lines.

Early response genes (ERGs) are a group of genes with low or absent expression in quiescent cells that can be induced rapidly by a variety of proliferation and differentiation stimuli. c-jun and c-fos are prototypes for this group of genes. Recent evidence suggests that DNA damaging agents such as cytotoxic drugs and ionizing radiation can elicit strong ERG induction, suggesting that these genes may be involved in DNA damage repair and/or cell death. Paralleling this interest in drug-induced ERG expression is a growing body of evidence implicating ERG expression as important to the intrinsic function of the central nervous system. We therefore set out to explore the pattern of chemotherapeutic drug- and radiation-induced c-jun and c-fos expression in neuroectodermally (astrocytic) derived cell lines. We have demonstrated that various chemotherapeutic agents and ionizing radiation can induce c-jun in a time- and concentration-dependent manner. Furthermore, this induction can be prevented by pretreatment of the cells with agents that protect against DNA damage. Finally, we have demonstrated that c-fos and c-jun expression and induction are discoordinately regulated, reflecting a difference in astrocytic cell lines compared to hematopoietic cell lines. The possible relevance of these observations to the clinical resistance of astrocytic tumors to standard chemotherapy and radiation is discussed.

Astrocytoma↗
PubMed1993

Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults.

BACKGROUND: The value of chemotherapy after standard postoperative external beam radiation in the treatment of malignant gliomas remains controversial. Despite recent recommendations from the Brain Tumor Cooperative Group that chemotherapy should be considered part of the standard treatment of patients with high-grade astrocytomas, several recent trials have questioned the efficacy of this approach. METHODS: Using results from 16 randomized clinical trials involving more than 3000 patients, the authors compared the survival rates of patients who received radiation alone or radiation with chemotherapy. The combined data were analyzed using the statistical method of meta-analysis as described by DerSimonian and Laird. RESULTS: The estimated increase in survival for patients treated with combination radiation and chemotherapy was 10.1% at 1 year (95% confidence interval, 6.8, 13.3%) and 8.6% at 2 years (5.2, 12.0%). These absolute increases in survival (treated-control [TC]) in patients treated with chemotherapy represent relative increases (T-C)/C of 23.4% at 1 year (15.8, 30.9%) and 52.4% at 2 years (31.7, 73.2%). This survival advantage is conferred by several different chemotherapeutic agents. When the prognostic variables of age and histology are factored into the analysis, however, the data suggest that the survival benefit from chemotherapy occurs earlier in patients with anaplastic astrocytoma (AA) than in patients with glioblastoma. CONCLUSIONS: The authors concluded that chemotherapy is advantageous for patients with malignant gliomas and should be considered part of the standard therapeutic regimen. Additional randomized trials using optimal radiation and chemotherapy may still be needed to precisely define which subgroups of patients, based on prognostic variables, will benefit most from chemotherapy after radiation.

Adult↗
PubMed1993

Complications of therapy for venous thromboembolic disease in patients with brain tumors.

Venous thromboembolic disease is a frequent complication in patients with intracranial malignancies. Because these patients are often perceived to be at increased risk of intracranial hemorrhage with anticoagulation, inferior vena cava (IVC) filters are frequently used in their treatment. We reviewed the records of 49 patients with intracranial malignancies and venous thromboembolic disease to determine the effectiveness of, and the complications resulting from, treatment. Of the 42 patients receiving IVC filters, a strikingly high percentage (62%) developed complications. Twelve percent developed recurrent pulmonary embolism, while 57% developed either IVC or filter thrombosis, recurrent deep venous thrombosis, or post-phlebitic syndrome. These complications severely reduced the quality of life of the affected patients. Only 15 of our patients were treated with anticoagulation, and seven of these received it because of continued thromboembolic disease. None of these 15 patients had proven hemorrhagic complications. This study suggests that the complication rate of IVC filters in patients with brain tumors is higher than commonly perceived and may outweigh the risk of anticoagulation.

Anticoagulants↗
PubMed1993

Effect of Bcl-2 on ionizing radiation and 1-beta-D-arabinofuranosylcytosine-induced internucleosomal DNA fragmentation and cell survival in human myeloid leukemia cells.

1-beta-D-Arabinofuranosylcytosine (ara-C) is an anti-leukemic agent that incorporates into cellular DNA leading to inhibition of DNA synthesis and loss of clonogenic survival. In contrast, ionizing radiation induces DNA damage through the generation of reactive oxygen intermediates. Although little is known of the specific determinants of ara-C and ionizing radiation-induced cytotoxicity, recent work has shown that both are capable of inducing internucleosomal DNA fragmentation in a pattern consistent with programmed cell death (apoptosis). In order to assess the importance of apoptosis in drug and ionizing radiation-induced cytotoxicity in the U-937 myelomonocytic cell line, we created cell lines that constitutively express a transfected bcl-2 gene. Bcl-2 was capable of inhibiting 40-50% of the ara-C and ionizing radiation-induced internucleosomal DNA fragmentation at all tested concentrations. However, cell survival following exposure to these agents was only increased in the bcl-2 transfectants at relatively low doses of ara-C and ionizing radiation. These data demonstrate that although bcl-2 is capable of inhibiting ara-C and ionizing radiation-induced DNA fragmentation in myeloid cells, it increases cell survival only at low doses of these agents. This suggests that apoptosis may be a less important mechanism of cytotoxicity at higher doses of ara-C and ionizing radiation than it is at lower doses.

Cell Survival↗