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Biomedical subjects

G J Vosika

Publications and source records attributed to G J Vosika.

At least 19 recordsLinked to original sources
PubMed1991

Phase I trial of ImmTher, a new liposome-incorporated lipophilic disaccharide tripeptide.

A phase I clinical trial was conducted to evaluate the toxicology and biological activity of a new liposome-incorporated lipophilic disaccharide tripeptide, ImmTher. Twelve patients with advanced nonhematological malignant disease received 13 courses of therapy at dose levels of 200-1,200 micrograms/m2. A course of therapy consisted of once-weekly administration of the drug for 2-12 weeks. The major clinical toxicities observed were chills and hypotension. No renal, hepatic, cardiac, or hematological toxicity was observed. A small decrease in pulmonary diffusion capacity was observed. Biological activity was demonstrated by changes in plasma cytokine levels, changes in in vitro monocyte cytotoxicity, and by a decrease in tumor size. Improvement was observed in three of three patients with metastatic disease to the liver. Response in these three patients correlated with an increase in their tumor necrosis factor and neopterin levels compared with nonresponders. These preliminary indications of biological and clinical activity of a liposome-incorporated lipophilic disaccharide tripeptide in patients with advanced metastatic hepatic disease suggest a potential new therapeutic approach to this common problem.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Immunologic and toxicologic study of disaccharide tripeptide glycerol dipalmitoyl: a new lipophilic immunomodulator.

A new lipophilic immunomodulator, disaccharide tripeptide glycerol dipalmitoyl (DTP-GDP), has been synthesized and evaluated for its immunologic activity and toxicology. DTP-GDP alone or in liposomes is more effective as an adjuvant and in activating macrophages compared with muramyldipeptide (MDP). Preclinical studies demonstrate no evidence of toxicity, including vasculitis. DTP-GDP in liposomes has shown antitumor activity in phase I clinical trials.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Phase-I study of intravenous modified lipid A.

Endotoxin and the lipid-A portion of the molecule have a variety of biological effects, including the induction of necrosis and regression of malignancy. To date extensive clinical trials of endotoxin as a potential therapeutic agent have been shunned due to the toxicity of the material. Several lipid-A analogues have been described which have reduced toxicity and retain antitumor activity. We have investigated in a phase-I trial the clinical toxicity and immunological effects of monophosphoryl lipid A prepared from Salmonella typhimurium and Salmonella minnesota. Patients entered on the study received IV monophosphoryl lipid A twice weekly for a total of 4 weeks. At least three patients were entered sequentially at each of the dose levels of 10, 25, 50, 100, and 250 micrograms/m2 body surface area. One patient was treated at the dose level of 500 micrograms/m2. The major clinical toxicity was fever, chills, and rigor, which occurred in over 50% of the treatments at doses of 250 micrograms/m2. Two instances of bronchospasm occurred in one patient who received 250 micrograms/m2. One patient received 500 micrograms/m2 and became hypotensive. Sequential clinical data showed no evidence of renal or hepatic toxicity. A transient decrease in the WBC and platelets occurred during the first 24 h after therapy. Immune function testing measured T cells, monocyte cytostasis, monocyte suppressor cell activity, and NK activity. These data suggested a shift in monocyte populations with activated cells moving into the tissue. Direct objective antitumor activity or necrosis was not observed in this group of patients. We conclude that monophosphoryl lipid A can be given to patients in a dose of up to 100 micrograms/m2 with acceptable toxicity. Its clinical activity as a single agent in combination with other immunomodulators remains to be demonstrated.

Animals↗
PubMed1983

Clinical immunotherapy trials of bacterial components derived from Mycobacteria and Nocardia.

Preparations of oil-attached mycobacterial components have been used in place of viable bacille Calmette-Guérin (BCG) in animal models and humans as a cancer immunotherapeutic agent. Most preparations consist of the isolated mycobacterial cell wall or cell wall skeleton attached to oil. Cord factor (trehalose dimycolate) has also been included in some preparations. In animal models, such preparations given intralesionally, systemically, or as a vaccine can cause regression of disease and establish tumor-specific immunity. Trials in humans have utilized oil-attached mycobacterial components given intralesionally, intradermally, intrapleurally, intraperitoneally, intravenously, and as an ointment. The major toxicity has been fever, chills, and local inflammation and/or abscess formation. An increase in the white blood count and lymphocyte count has been observed. An increase in liver function test was reported in a minority of patients. Given intralesionally, these preparations cause regression of the injected lesion, regression of noninjected cutaneous and visceral disease, and the apparent establishment of a tumor-specific immune response. Administered intrapleurally and intraperitoneally, there is a response and a clearing of malignant cells in approximately 50% of cases. Given intravenously, oil-attached cell wall skeleton and trehalose dimycolate can eradicate pulmonary disease. Used as an ointment, the preparations have been effective in mycosis fungoides and Kaposi's sarcoma. These reagents demonstrate definite single-agent activity. This was most prominent in patients who were immunocompetent and who had immunogenic tumors such as malignant melanomas. The reagents represent potent immunotherapeutic agents with acceptable toxicity. Further trials of these and subsequent refined preparations are warranted.

Antigens, Bacterial↗
PubMed1983

Vindesine for metastatic malignant melanoma. A phase II trial.

Sixteen patients, 13 of whom had received prior chemotherapy, were treated with vindesine for advanced malignant melanoma. Previous treatment included vinca alkaloids in six. Thirteen patients received vindesine, 4 mg/m2 and three received vindesine, 3 mg/m2 by weekly I.V. injection. There were two partial (12%) and no complete responses among all of the patients. Both responses occurred in subcutaneous lesions and lasted for 4 and 6 weeks, respectively. Fifteen patients could be evaluated for treatment-related toxicity. The most common side effect was modest leukopenia (less than 3000/microliter) in 10 patients (67%). The lowest leukocyte count recorded was 1100/microliter. Thrombocytopenia was not encountered. Neurotoxicity, manifest most commonly as mild or moderate peripheral paresthesiae, was seen in eight patients (53%).

Adult↗
PubMed1983

Phase I study of iv mycobacterial cell wall skeleton and cell wall skeleton combined with trehalose dimycolate.

A phase I study to determine the toxicity and immunologic effects of iv administered aqueous suspensions of mycobacterial cell wall skeleton (CWS) and CWS combined with trehalose dimycolate (TDM) was performed. A total of 26 patients received suspensions of either CWS or CWS/TDM given iv every 1 or 2 weeks in set doses of either 100, 250, 500, or 1000 micrograms/m2. The major dose-limiting side effects for both preparations were fever and chills at a dose of 1 mg/m2. This was more severe with the combined CWS/TDM. There was no renal or pulmonary toxicity. There was evidence of hepatic toxicity, with increases in the alkaline phosphatase and gamma glutamyl transferase, especially with high doses of CWS/TDM. Both the CWS and CWS/TDM groups had an increase in their wbc count. In the patients receiving CWS alone, there was a decrease in the peripheral blood monocytes. In the CWS/TDM group, there was an increase in the serum lysozyme, suggesting macrophage activation. No antitumor effect was seen in this phase I study. Aqueous suspensions of CWS and CWS/TDM can be administered safely iv over a period of time, with evidence of an effect on hematologic parameters.

Animals↗
PubMed1982

Vindesine in bronchogenic carcinoma: a phase II trial.

Twenty-seven patients with advanced bronchogenic carcinoma were treated with vindesine, 3 mg/m2/week. Twenty-three patients were evaluable for response. Two of six patients with small-cell carcinoma and one of 17 patients with non-small-cell carcinoma had partial responses. Two other patients with non-small-cell carcinoma had minor responses. The duration of the responses was 2-4 months. Neurologic toxicity occurred in 14 patients and was mild except in two patients. There was a median hemoglobin fall of 2.2 g/dl and a median leukocyte nadir of 2800/microliter during vindesine therapy. Thrombocytopenia occurred in 2 patients and mild thrombocytosis occurred in 10 patients. Seven patients experienced phlebitis or cellulitis at the site of drug administration which could be prevented with small doses of intravenous methylprednisolone. These results suggest that vindesine is well tolerated and possesses some activity in patients with previously treated bronchogenic carcinoma.

Adenocarcinoma↗
PubMed1981

Clinical trials with diglycoaldehyde (NSC-118994): review and reasons for withdrawal from clinical trial.

All Phase II studies with diglycoaldehyde with leukemia and solid tumors have been reviewed. The dose schedules employed ranged from 1.5 to 2.0 g/m2/day for 3 to 5 days. The most common side effects have been gastrointestinal (nausea and vomiting), which occurred in 22% of the patients. Renal toxicity (rise in BUN, creatinine, and urinary proteins) was seem in 17% of the patients treated. Other infrequent toxicities include hypocalcemia (9%) and local complications such as phlebitis. Leukopenia, thrombocytopenia, positive Coombs' test and impairment in coagulation profile were also reported. In contrast to the hints of therapeutic efficacy described during Phase I trials, in phase II trials no activity was noted among 96 patients with solid tumors and only minimal antileukemic action among 49 other patients. These disappointing Phase II trials coupled with prominent toxicities have prompted the decision to terminate further clinical testing. This report summarizes all clinical observations as an example of circumstances which curtail clinical testing of anticancer drugs.

Aldehydes↗
PubMed1980

Comparison of tamoxifen and hypophysectomy in breast cancer treatment.

The effectiveness of hypophysectomy and tamoxifen in treating advanced breast cancer was compared in a randomized study of 26 patients who had responded to prior oophorectomy or additive hormonal therapy. When patients failed to respond or relapsed from tamoxifen or hypophysectomy, the therapy was crossed over. In this designed sequence, the rate and duration of response observed with tamoxifen or hypophysectomy used as the first regimen were comparable. The results suggest that tamoxifen is effective in the posthypophysectomy phase and the sequence or hypophysectomy followed by tamoxifen in hormone-dependent breast cancer is preferable to achieve a maximal control of the disease.

Adult↗
PubMed1979

Analysis of the genetic complexity and abundance classes of messenger RNA in human liver and leukemic cells.

In an effort to determine the number of genes expressed as messenger RNA in disparate human tissues we have analyzed the genetic complexity of the polyribosome-associated poly(A)-containing RNA population obtained from liver and lymphoblastic leukemic cells. This was accomplished by measuring the kinetics of hybridization of mRNA to a complementary DNA probe synthesized by avian myeloblastosis virus reverse transcriptase in vitro. The results obtained from such an analysis revealed the presence of two major abundance classes of mRNA with a total genetic complexity of approximately 10,000 diverse mRNA species in both of these cell types. Diversity of mRNA species in these unrelated human cells was studied by heterologous hybridization reactions between the cDNA of one cell type and a vast excess of poly(A)-containing mRNA from another. These types of studies indicated that extensive homology (more than 80%) exists in the mRNA sequences of disparate human cell types and suggest that the vast majority of genetic information expressed as mRNA is required for the maintenance of cellular functions common to functionally different human tissues.

Avian Myeloblastosis Virus↗
PubMed1979

Intralesional immunotherapy of malignant melanoma with mycobacterium smegmatis cell wall skeleton combined with trehalose dimycolate (P3).

The clinical efficacy of intralesional immunotherapy utilizing Mycobacterium smegmatis cell wall skeleton (CWS) and trehalose dimycolate attached to oil droplets was investigated in 15 patients with advanced malignant melanoma. Patients received 300 microgram to 1050 microgram of the CWS combined with one-half that amount of trehalose dimycolate every 1 to 2 weeks for a total of 8 treatments. Therapy was continued if regression of injected lesions only occurred. Therapy was discontinued if regression of noninjected disease also occurred. Six of the 15 patients had regression of at least one injected lesion. Four of these 6 patients also had regression of noninjected disease lasting 4+, 6, 16 and 18+ months. Response was highly related to immune status. Six (83%) of 7 patients who reacted to one of a battery of skin tests responded. All 8 patients who did not react to skin tests failed to respond to therapy. There was no correlation of response with sex, prior therapy, disease-free interval or presence of visceral disease. Mycobacterial CWS and trehalose dimycolate is an effective immunotherapeutic agent. Additional studies of purified immunoadjuvants are warranted.

Cell Wall↗
PubMed1978

CCNU-adriamycin therapy in bronchogenic carcinoma.

Forty-eight patients with advanced bronchogenic carcinoma were treated with a combination of CCNU and Adriamycin. There was an overall objective response rate of 38%. This consisted of 1 of 12 (8%) patients with epidermoid carcinoma, 5 of 15 (33%) with adenocarcinoma, 2 of 5 (40%) with large cell undifferentiated carcinoma and 10 of 16 (63%) with small cell undifferentiated carcinoma. The overall median survival time (MST) from initiation of therapy was 28 weeks. The MST was 18 weeks for patients with epidermoid carcinoma, 30 weeks for those with adenocarcinoma, 39 weeks for those with large cell carcinoma, and 30+ weeks for those with small cell carcinoma. Objective tumor response was associated with prolonged survival. There were no drug related deaths and toxicity was minimal.

Adenocarcinoma↗
PubMed1978

CCNU, vinblastine, and delalutin therapy in renal cell carcinoma.

Advanced renal cell carcinoma is relatively resistant to most adequately evaluated chemotherapeutic agents. The combination of CCNU and vinblastine, which has antitumor activity in a frog renal carcinoma model system, has demonstrated activity in initial studies in man. The current study investigated this combination of drugs together with a progestational agent, Delalutin. Seventeen patients with metastatic renal cell carcinoma were treated with CCNU, vinblastine and Delalutin. There were no objective responses. Four patients with stable disease had a mean survival of 18 months compared to 13 patients with progressive disease who had a mean survival of 5 months. The survival of the four patients with stable disease was in large part due to the slowly progressive natural history of their disease.

Adenocarcinoma↗
PubMed1978

Studies on the transformation of rat embryo cells of low passage by carcinogenic fluorenylhydroxamic acids and their acetate esters.

Rat embryo cells of low passage subjected to a single treatment with certain carcinogenic fluorenylhydroxamic acids and their respective acetate esters showed signs of transformation in vitro, such as changes in phenotype, growth in soft agar and agglutination with concanavalin A. In addition, certain changes in karyotype and loss of diploidy were observed. There was no evidence, either by electron microscopy or by assay of RNA-dependent DNA polymerase, for the presence of virus. None of these cell lines produced tumors after inoculation into the isologous host. The results of these study lead us to suggest that malignant transformation is a multistep process and that certain criteria of transformation of rat embryo cells are associated with the initial stage(s) in which the cells are transformed without being tumorigenic. The ultimate test for malignant transformation of rat embryo cells remains the production of tumors in a susceptible host after inoculation of treated cells.

Agglutination Tests↗
PubMed1975

Oncornavirus-like particles from cultured bone marrow cells preceding leukemia and malignant histiocytosis.

Particles with the density and enzymatic activity characteristic of known oncornavirus have been previously described in bone marrow cells from patients with leukemia in relapse and in remission. We have confirmed these findings and studied two patients in whom preleukemia was among the diagnostic considerations. Following cultivation of bone marrow from these patients for 1 week in conditioned media with dexamethasone, a high-speed pellet of the supernatant fluid and disrupted cells was prepared and analyzed on a sucrose gradient for enzymatic activity characteristic of RNA-directed DNA polymerase (reverse transcriptase). Peaks of endogenous DNA polymerase activity showing ribonuclease sensitivity and/or stimulation with the synthetic template poly(rC)-(dG)12-18 were demonstrated in both patients at densities of 1.15 to 1.19 and 1.21 to 1.24 g/ml. Subsequently, diagnosis 2 and 4 months after initial evaluation revealed acute myelogenous leukemia and malignant histiocytosis, respectively. Prior studies have suggested a possible etiological significance of such particles in human leukemia. The demonstration of similar particles preceding clinically overt disease in these patients supports this hypothesis and offers the possibility of early diagnosis and treatment.

Adolescent↗