Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A clinical trial of the oral form of VP 16-213 (NSC-141540), a semisynthetic podophyllotoxin, was undertaken. In 20 patients, treatment was started at 200 mg/day p.o. for 5 days; courses were repeated after a rest period of 16 days. Five patients were treated at the same dose, repeated with only 9-day rest periods. Subsequently, 65 patients were given 300-400 mg/day for 5 days, with rest periods of 9 days between courses. The side effects encountered included anorexia, nausea and vomiting, stomatitis, diarrhea, leukopenia, thrombocytopenia, alopecia, and pruritus. Substernal discomfort with or without palpitations was reported by 18 patients; no explanation for this symptom could be found. No complete remissions (CR) were observed. Parital remissions (PR) and improvement (IMP) were seen as follows: small cell carcinoma, lung (10 patients)--2 PR, 3 IMP; adenocarcinoma, lung (4 patients)--1 PR; alveolar cell carcinoma, lung (1 patient)--1 IMP; mesothelioma (4 patients)--1 IMP; ovarian cancer (12 patients)--3 PR, 3 IMP; breast cancer (20 patients)--4 IMP; colon cancer (8 patients)--2 IMP; bladder cancer (4 patients)--2 IMP; histiocytic lymphoma (7 patients)--2 PR, 3 IMP; chronic myeloid leukemia (1 patient)--1 IMP.
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PMID:A clinical trial of the oral form of 4'-demethyl-epipodophyllotoxin-beta-D ethylidene glucoside (NSC 141540) VP 16-213. 16 75

The past year has seen important advances in our understanding of the molecular biology of human cancer. We have learned more about how normal genes with critical functions in growth and development can induce cellular transformation and malignancy if mutated or overexpressed. The finding of such oncogenes in specific human cancers often portends a poor prognosis. We have learned more about tumor suppressor genes, whose loss by mutation, deletion, or translocation can lead to cancer. A series of defects involving both oncogenes and tumor suppressor genes has been shown to characterize the multistep development of a fully malignant colon cancer. We have new insights into the promotion of malignancy by the fused gene product resulting from the chromosomal abnormality diagnostic of one leukemia, chronic myelogenous leukemia. Recently, in acute promyelocytic leukemia, a characteristic chromosomal abnormality has been shown to result in a specific fusion of a nuclear receptor that activates transcription and a previously unknown gene. Most interestingly, a ligand for this rearranged receptor has been shown to be a novel effective treatment for the disease. This review summarizes many of these advances.
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PMID:Oncogenes and clinical oncology. 164 34

Our expanding knowledge of the immune system has provided a basis of rationality for immunotherapy. Some non-specific immunotherapy has achieved the status of standard treatment: interferon in hairy cell leukemia and chronic myelogenous leukemia, BCG in bladder cancer, and levamisole in colon cancer adjuvant therapy. Tumor infiltrating lymphocytes, moreover, offer a level of specificity heretofore unknown. Combined with the newly available synthetic cytokines that regulate the normal immune system there is the potential for a major breakthrough in biotherapeutics. Problems remain. We have yet to identify tumor antigens with the precision necessary for effective immunotherapy. Indeed, we have no assurance that tumors will regularly synthesize new antigens. In the broad spectrum of immune deficiency syndromes, we have yet to see an increase in the common epithelial tumors that account for the great bulk of human cancer. This suggests that we still have a great deal more to learn.
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PMID:Immunotherapy of cancer with lymphokines and lymphokine-activated killer cells. 192 49

Twenty-five patients with disseminated cancer (nine with renal cell carcinoma, five with melanoma, three with Hodgkin's lymphoma and chronic myelocytic leukemia [CML], two with soft tissue sarcoma, one each with large-cell lymphoma, breast cancer, and colon cancer), 13 males and 12 females, aged 25 to 68, were treated with recombinant human interleukin-2 (rIL2) by continuous infusion and adoptive transfer of autologous lymphocytes activated in vitro with IL2. Patients underwent leukapheresis on days 1, 8, 15, and 22 of the treatment. Cells, bulk activated for 20 hours in serum-free culture medium with 1,000 U IL2/mL in transfusion transfer packs as culture vessels, were transfused the following day. The infusion of IL2 by continuous infusion for six days started immediately after each adoptive transfer for 4 weekly courses. The dose of IL2 was escalated weekly in each patient; starting doses of IL2 were also escalated in subsequent cohorts of patients until maximally tolerated doses were reached. Nine patients had objective tumor regressions (three with renal cell cancer, two with Hodgkin's lymphoma, and one each with melanoma, sarcoma, breast, and colon cancer). Six responses were partial, two were minor, and one was mixed. Responding patients were maintained with IL2 by continuous infusion for six days every 6 to 8 weeks, without adoptive cell transfer. The median duration of responses was 16 weeks (3 to 60 + weeks). Tumor regression was related to the dose of IL2 (greater than or equal to 3.4 x 10(6) U/m2/d for six days) and to the in vivo lymphoproliferative effects of the lymphokine, but not to the total number of cells adoptively transferred. Side effects of treatment were transient and quickly reversible. Renal, hepatic dysfunction, and dyspnea were directly related to the dose of IL2 and to lymphocytosis. Other toxicities were mild hypotension with mild fluid retention, oral mucositis, anemia, thrombocytopenia, fever, and fatigue.
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PMID:Recombinant interleukin-2 by continuous infusion and adoptive transfer of recombinant interleukin-2-activated cells in patients with advanced cancer. 266 33

Mortality up to 1 January 1983 has been studied in 14,106 patients with ankylosing spondylitis given a single course of X-ray treatment during 1935-54. For neoplasms other than leukaemia or colon cancer, mortality was 28% greater than that of members of the general population of England and Wales, and this increase is likely to have been a direct consequence of the treatment. The proportional increase reached a maximum of 71% between 10.0 and 12.4 years after irradiation and then declined. There was only a 7% increase in mortality from these tumours more than 25.0 years after irradiation and only for cancer of the oesophagus was the relative risk significantly raised in this period. Neither the magnitude of the relative risk, nor its temporal pattern following treatment, were greatly influenced by the age of the patient at first treatment. For leukaemia there was a threefold increase in mortality that is also likely to have been due to the radiotherapy. The relative risk was at its highest between 2.5 and 4.9 years after the treatment and then declined, but the increase did not disappear completely, and the risk was still nearly twice that of the general population more than 25.0 years after treatment. There was some evidence that the risks of acute myeloid, acute lymphatic, and chronic myeloid leukaemia were all increased, but no evidence of any increase in chronic lymphatic leukaemia. The relative risk appeared to be greatest for acute myeloid leukaemia. For colon cancer, which is associated with spondylitis through a common association with ulcerative colitis, mortality was increased by 30%. For non-neoplastic conditions there was a 51% increase in mortality that was likely to be associated with the disease itself rather than its treatment. The increase was apparent for a wide range of diseases and was not confined to diseases that have been associated clinically with ankylosing spondylitis.
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PMID:Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis. 381 87

The effects of sublethal radiation (3 Gy) and anti-asialo GM1 (anti-ASGM1) on engraftment of human tumour cell lines and fresh tumour were evaluated in the severe combined immunodeficient (SCID) mouse. Four tumour cell lines (colonic adenocarcinoma LS174T, malignant melanoma MEWO, lung adenocarcinoma H125, chronic myelogenous leukemia K562) and a fresh colon cancer metastasis were injected subcutaneously, intraperitoneally or intravenously into SCID mice. Tumour volume and metastatic spread of implanted tumours were evaluated 3-8 weeks following inoculation. Pretreatment with radiation and anti-ASGM1 resulted in more rapid and extensive uptake of subcutaneous and intraperitoneal tumours. Tail vein injection into pretreated animals also resulted in a greater number of lung metastases of H125, MEWO and K562 cell lines. This study demonstrates that sublethal radiation and the elimination of murine NK cell activity with anti-ASGM1 improves tumour take rates. These findings should prove useful for investigations of human cancer immunotherapy using SCID mice engrafted with human lymphocytes and human tumours.
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PMID:Improved engraftment of human tumours in SCID mice pretreated with radiation and anti-asialo GM1. 784 29

The process of malignant transformation can be ascribed to a series of characteristics and definable mutations of genes which encode proteins that control cell growth and differentiation. During the course of malignant transformation the cancer-related genes are altered by a variety of mechanisms including translocations, deletions, and point mutations which commonly result in the expression of aberrant proteins. Our laboratory has focused on determining the extent to which cancer-specific proteins expressed by aberrant cancer-related genes can function as tumor-specific antigens. The current paper reviews our studies with two prototype cancer-specific proteins, mutated p21ras protein and chimeric p210bcr-abl protein. Ras protooncogenes are activated by point mutation in approximately 20% of human malignancies. The mutations occur primarily at codons 12 or 61 and result in the expression of p21ras proteins with single substituted amino acids. Only a limited number of amino acid substitutions occur. Murine studies demonstrate that immunization with synthetic peptides corresponding to the mutated segment can elicit both class II restricted CD4+ helper/inducer T-cell responses and class I restricted CD8+ cytotoxic T-cell responses specific for mutated p21ras protein. In addition, the existence in vivo of tumors expressing mutated ras proteins can be detected by assaying for T-cell immunity to the mutated segment of ras protein. Preliminary human studies show that some patients with colon cancer have existent antibody responses to p21ras protein, implying the possible existence of autochthonous T-cell immunity to mutated ras proteins in those patients. In chronic myelogenous leukemia the human c-abl protooncogene from chromosome 9 is translocated to the specific breakpoint cluster (bcr) region on chromosome 22. The translocation results in the formation of a bcr-abl fusion gene that encodes at 210-kD chimeric protein. The joining region segment of chimeric bcr-abl protein is composed of a unique combination of c-abl and bcr amino acids and is expressed only by malignant cells. Studies demonstrate that immunization of mice with synthetic peptides corresponding to the joining region segment can elicit class II restricted CD4+ T-cell responses to p210bcr-abl proteins. Preliminary studies show that bcr-abl peptides can bind in the groove of both murine and human class I MHC molecules and can elicit bcr-abl peptide-specific cytotoxic T lymphocytes (CTL). Whether bcr-abl peptide-specific CTL can lyse cells expressing bcr-abl protein is a yet unknown. In summary, the results of the studies reviewed confirm that cancer-specific oncogenic proteins can serve as tumor-specific antigens.
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PMID:T-cell immunity to oncogenic proteins including mutated ras and chimeric bcr-abl. 810 58

A total of 22 genes have been identified in the carcinoembryonic antigen (CEA) gene family. The protein products of this family are highly homologous and include CEA, biliary glycoprotein, nonspecific cross-reacting antigen 50/90 (NCA 50/90), NCA 95, and pregnancy-specific beta-glycoprotein. We used a monoclonal antibody with high affinity to develop a specific enzyme-linked immunosorbent assay (ELISA) method for NCA 50/90 in serum and plasma. Our calibrators were based on affinity-purified recombinant protein from a baculovirus expression system. No significant reactivity with purified CEA, recombinant NCA 95, or recombinant biliary glycoprotein was found by Western blot analysis or in the ELISA method. Only 1 of 15 sera from pregnant women (chorionic gonadotropin > 1000 ng/ml) was positive in the NCA 50/90 ELISA, suggesting that this method does not detect pregnancy-specific glycoprotein. A cutoff value of 18 ng/ml was established based on the 95% value of serum and plasma from 147 healthy volunteers. Only 3 of 31 serum and plasma samples from patients with clinically inactive breast cancer were elevated above the cutoff value, but 44% of 136 samples from patients with clinically active breast cancer were positive. NCA 50/90 measurements were elevated in 7 of 25 patients with active breast cancer whose CEA and CA 15-3 values were below cutoff, and NCA 50/90 values do not correlate with CEA in breast cancer. In addition, we found sensitivities of 70, 39, and 42% for lung cancer, colon cancer, and leukemia, respectively. The sensitivity for non-small cell lung cancer was 85%, however, compared to 50% for small cell lung cancer. Serum from leukemia patients showed an overall sensitivity of 43%, but 71% (10 of 14) sera from patients with chronic myelogenous leukemia were positive compared to, for example, chronic lymphocytic leukemia where 0 of 7 sera had NCA 50/90 values above the cutoff. These studies suggest that NCA 50/90 may have clinical utility in the management of patients with a variety of cancers.
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PMID:Nonspecific cross-reacting antigen 50/90 is elevated in patients with breast, lung, and colon cancer. 811 11

The occurrence of multiple malignancy was studied in 674 patients with hematologic malignancies who were admitted to this department during the past 10 years. Of the 674 patients, 205 were aged 65 years or older, and 56 (8.3%) had another cancer. The frequency of multiple malignancy was significantly higher in older patients than in younger patients: 44 (21.5%) vs. 12 (2.6%). The major hematologic conditions in patients with multiple malignancy were multiple myeloma, myelodysplastic syndromes, non-Hodgkin's lymphoma, and chronic myelogenous leukemia. The major sites of cancers other than hematological malignancies were the stomach, colon, breast, and esophagus. Many of the older patients had gastric cancer or colon cancer, and gastric cancer was common in the younger patients. The multiple malignant neoplasms were synchronous in as many as 20 of the 44 older patients. There was only one such case among the younger patients. Of the 56 patients, nine had received alkylating agents, and one has received etoposide. In brief, elderly patients with hematologic malignancies are likely to have multiple malignant neoplasms. If they are synchronous, the patient's prognosis may be adversely affected, because simultaneous management of multiple malignant neoplasms is not easy.
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PMID:[Double cancer in elderly patients with hematologic malignancies]. 875 14

The human genome contains at least 50 copies of the human endogenous retrovirus K (HERV-K) family which is related to the mouse mammary tumor virus (MMTV). Some members have been shown to be transcriptionally active and to have large open reading frames. Using the RT-PCR method we have investigated the HERV-K env transcription pattern in several malignant tissues and in peripheral blood mononuclear cells PBMCs). Samples were derived from chronic myelogenous leukemia (CML), breast cancer, colon cancer, high and low grade non-Hodgkin's lymphomas, Hodgkin's disease, myelodysplastic syndrome, thyroid adenoma (TA) and from PBMCs of patients with breast cancer, gastric cancer, and of healthy individuals. We found abundant HERV-K env transcripts in all tissues under investigation. Using HERV-K 10 specific primers for amplification we detected in addition to transcripts with high homology to HERV-K 10 (ca. 96% homology on the amino acid level) also transcripts of low homology to HERV-K10 (ca. 71%). Interestingly, all solid tissues containing high percentages of malignant cells such as breast cancer, colon carcinoma, low and high grade non-Hodgkin's lymphomas showed exclusively HERV-K env related transcripts with low homology to HERV-K 10. In contrast, in samples containing only a low proportion of malignant cells or no malignant cells at all we observed both types of transcripts. Thus, our data suggest that the expression pattern of HERV-K elements in human cells is very heterogenous and subjected to a complex transcriptional regulation.
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PMID:Two groups of endogenous MMTV related retroviral env transcripts expressed in human tissues. 942 77


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