Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Altered structure and regulation of the c-myc proto-oncogene have been associated with a variety of human tumours and derivative cell lines, including Burkitt's lymphoma, promyelocytic leukaemia and small cell lung cancer (SCLC). The N-myc gene, first detected by its homology to the second exon of the c-myc gene, is amplified and/or expressed in tumours or cell lines derived from neuroblastoma, retinoblastoma and SCLC. Here we describe a third myc-related gene (L-myc) cloned from SCLC DNA with homology to a small region of both the c-myc and N-myc genes. Human genomic DNA shows an EcoRI restriction fragment length polymorphism (RFLP) of L-myc defined by two alleles (10.0- and 6.6-kilobase (kb) EcoRI fragments), neither associated disproportionately with SCLC. Mouse and hamster DNAs exhibit a 12-kb EcoRI L-myc homologue, which indicates conservation of the gene in mammals. Gene mapping studies assign L-myc to human chromosome region 1p32, a location distinct from that of either c-myc or N-myc but associated with cytogenetic abnormalities in certain human tumours. This L-myc sequence is amplified 10-20-fold in four SCLC cell line DNAs and in one SCLC tumour specimen taken directly from a patient. Either the 10.0- or 6.6-kb allele can be amplified and in heterozygotes only one of the two alleles was amplified in any SCLC genome. SCLC cell lines with amplified L-myc sequences express L-myc-derived transcripts not seen in SCLC with amplified c-myc or N-myc genes. In addition, some SCLCs without amplification also express L-myc-related transcripts. Together, these findings suggest an enlarging role for myc-related genes in human lung cancer and provide evidence for the concept of a myc family of proto-oncogenes.
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PMID:L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. 299 22

Six of 796 patients treated with intensive combination chemotherapy for small cell carcinoma of the lung developed overt acute nonlymphocytic leukemia (ANLL) (three patients) or preleukemia with severe refractory cytopenia and clonal cytogenetic abnormalities in bone marrow cells (three patients). The latent period to development of preleukemia or leukemia was less than two years in four of the six patients. The cumulative risk of preleukemia and leukemia according to a Kaplan-Meier estimate was 14.0% +/- 6.9% (mean +/- SE) four years after the start of treatment. The relative risk of overt ANLL was 77, since three cases were observed v 0.039 cases expected, based on the age- and sex-specific incidence of acute nonlymphocytic leukemia in the general Danish population. The risk of secondary solid tumors was not increased. The possible causes of the exceptionally early appearance and very high cumulative risk of leukemic complications found in the present study, as compared to previous experience in other malignant diseases, is discussed, including the implications for future therapy of patients with small cell lung cancer.
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PMID:Acute nonlymphocytic leukemia, preleukemia, and solid tumors following intensive chemotherapy of small cell carcinoma of the lung. 299 12

From 1977 to 1982, 377 patients with small cell lung cancer were treated at Vanderbilt University Medical Center. All patients received combination chemotherapy consisting of cyclophosphamide, doxorubicin, and vincristine (CAV) with or without methotrexate, etoposide, and/or hexamethylmelamine. Thoracic and/or prophylactic cranial irradiation was administered to 159 (42 percent) and 192 (51 percent) patients, respectively. Acute nonlymphocytic leukemia was observed in two patients at 22 and 81 months from the start of therapy. The relative risk of leukemia was 154 (95 percent confidence limit, 38 to 293). A Kaplan-Meier estimate of the cumulative probability of leukemia was 1.9 +/- 1.4 percent seven years after the start of treatment. The relative risk of leukemia is significantly increased in this group of patients (p less than 0.0001). Acute nonlymphocytic leukemia is a long-term complication of small cell lung cancer therapy.
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PMID:Acute nonlymphocytic leukemia after treatment of small cell lung cancer. 302 77

We examined the activity reported in phase II trials for all cytotoxic drugs introduced into clinical trial by the National Cancer Institute (NCI) since 1970. For each drug in each tested tumor type we derived a response rate from the pooled data of all trials reported either in the literature or to the NCI. We rated a drug active if the lower 80% confidence bound of the response rate was greater than 10%. Of the 83 drugs developed and introduced by the NCI, there are 47 which we considered evaluable. Of these drugs, 24 were rated active in at least one cancer type, of which ten were analogs of drugs in wide clinical use. Diseases most commonly responsive include lymphoma (74% of the tested drugs rated active), leukemia (35%), urothelial cancer (29%), small cell lung cancer (29%), ovarian cancer (22%), cervical cancer (22%), and breast cancer (18%). For colon cancer and melanoma, only one of 42 and two of 30 tested drugs rated active, respectively. We also examined the completeness of clinical testing: among the 47 drugs there were 20 tested in greater than or equal to 14 patients with leukemia, 23 tested in patients with lymphoma, and 18 tested in patients with small cell lung cancer; whereas 34 drugs for breast cancer, 42 for colon cancer, and 33 for non-small cell lung cancer were more completely evaluated. Considering the "clinical panel" of seven cancer types (breast, non-small cell lung, small cell lung, colon, melanoma, leukemia, and lymphoma), drugs were tested in greater than or equal to 30 patients in a median of four tumor types. Testing in this panel failed to detect activity in only one drug found active in another tumor, although testing in diseases other than this clinical panel was even less complete. Phase II testing should emphasize completion of minimum accrual goals, testing in patient populations with minimum prior therapy, and evaluation in a minimum set of tumor types.
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PMID:Clinical drug development: an analysis of phase II trials, 1970-1985. 379 Dec 70

The purpose of this investigation was to examine factors which regulate the reprogramming of gene expression in tumors responsible for resistance to tiazofurin. To study the resistance phenomenon drug-induced tumor lines were selected and examined for the mechanism of resistance. A comparison of the biochemical expression of resistance to tiazofurin in drug-induced resistant lines of hepatoma 3924A, leukemias L1210 and P388 revealed that the 3 lines expressed similar genetic alterations related to reduced TAD content, decreased NAD pyrophosphorylase activity and increased synthesis of guanylates from salvaging preformed guanine indicating that these 3 factors play an important role in the resistance to tiazofurin. Resistance was stable in the leukemia lines and did not require drug to maintain resistance. Hepatoma 3924A resistant line reverted to sensitive state in the absence of drug selection pressure. NAD pyrophosphorylase activity was substantially deleted in the tiazofurin resistant leukemia lines, but was only significantly decreased in the hepatoma resistant line. Extensive biochemical alterations including enhanced activity of IMP dehydrogenase, increased inosinate and guanylate pools, and reduced uptake of tiazofurin were found in the hepatoma line resistant to tiazofurin. To examine the applicability of these results to naturally sensitive and spontaneously resistant tumors, murine tumors were examined. In murine tumors, TAD accumulation, ratios of enzyme activities responsible for the synthesis and degradation of TAD, and the ratios of perturbation of inosinate and guanylate pools following tiazofurin challenge demonstrated significant correlation with the sensitive or resistant nature of the tumors. To extrapolate these observations to human tumor systems, cytotoxicity of tiazofurin and its metabolic effects were compared in 6 human lung cancer cell lines derived from cancer patients with small cell lung cancer (4 lines) and lung adenocarcinoma (2 lines). Cell lines exhibiting greater sensitivity to tiazofurin accumulated significantly larger amounts of TAD and showed significant reduction of guanylate pools following tiazofurin incubation. The activity of the enzyme responsible for the formation of TAD, NAD pyrophosphorylase, did not correlate with responsiveness to tiazofurin but the enzyme which hydrolyzes TAD, TADase, correlated positively with the status of resistance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical mechanisms of resistance to tiazofurin. 383 25

Marrow transplantation is effective treatment for a number of hematological diseases in patients under the age of 50 who have an HLA-identical sibling donor. It is successful in the treatment of aplastic anemia with 70-85% long-term survival. It offers 10-30% apparent cures for patients with acute leukemia who have relapsed at least once, and for those with chronic myelocytic leukemia in blast crisis. Although still somewhat controversial, it appears to be the treatment of choice for patients with acute nonlymphoblastic leukemia in first chemotherapy induced remission, and for those with chronic myelogenous leukemia in the chronic phase since approximately 50-60% of these patients experience long-term, disease-free survival. Patients with acute lymphoblastic leukemia grafted in second or subsequent remission may expect a 30% "cure" of their disease. Marrow grafting is the only effective treatment for many patients with inherited immunologic deficiencies and certain genetic storage diseases. Cures of congenital Fanconi's anemia, Blackfan-Diamond anemia, osteopetrosis, paroxysmal nocturnal hemoglobinuria and thalassemia major have been achieved. Marrow transplantation is being explored for the therapy of patients with lymphoma, Hodgkin's disease, preleukemia, multiple myeloma, hairy cell leukemia, small cell lung cancer, testicular cancer, ovarian cancer and neuroblastoma. Marrow transplantation has been limited by the fact that many patients do not have HLA-identical siblings and very few have monozygotic twins. More recently, marrow transplants from HLA-nonidentical family members and even from unrelated donors have been successfully explored.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Marrow transplantation: the Seattle experience. 391 47

Clinical trials using interferon to treat human malignancies are currently hampered by limited supplies of the compound. We have utilized a human tumor cloning system as an assay for the antitumor effects of human leukocyte interferon. Interferon was tested against 62 patients' tumors growing in this soft agar system. A dose-dependent cytotoxic effect of interferon was noted against only five of the patients' tumors. A greater than or equal to 70% decrease in tumor colony-forming units (TCFUs) was noted with one lymphosarcoma cell leukemia, one small cell lung cancer, one adenocarcinoma of the lung, one breast cancer, and a pancreatic cancer. One patient had his tumor cultured in vitro and had a clinical trial with interferon. This patient whose tumor demonstrated in vitro sensitivity had a clinical antitumor effect with interferon therapy. The in vitro results in this study suggest that the human leukocyte interferon currently available has a low level of activity in a human tumor cloning system. Additional testing is needed to determine whether the cloning system can identify the patient(s) who might have an antitumor effect from the interferon.
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PMID:Activity of human leukocyte interferon in a human tumor cloning system. 617 27

Two human small cell lung carcinoma cell lines, NCI-H69 and NCI-H128, were used as alternating sources of immunogen to generate monoclonal antibodies to small cell lung carcinoma-associated antigens. BALB/c mice were sensitized with seven injections of live tumor cells, four with NCI-H69 cells and three with NCI-H128 cells. Somatic cell hybridization was performed by fusion of the immune murine splenocytes using syngeneic myeloma cells from the SP2/0 Ag14 cell line. Hybridoma colonies were screened against small cell lung carcinoma cells and normal lung fibroblasts with an enzyme-linked immunosorbent assay. Compared to animals immunized with only NCI-H69 or NCI-H128 cells, alternate immunization resulted in the generation of a significantly higher number of hybridomas that reacted selectively with both tumor cell lines. Monoclonal antibodies from two reactive hybrid clones generated by alternate immunization, SCLC 2051 and SCLC 5023, were uniformly negative to normal human tissues including lung, kidney, liver, spleen, breast, thyroid, brain, small intestine, and colon. While both monoclonal antibodies were nonreactive to paraffin-embedded, formalin-fixed, nonmalignant lung biopsies, the monoclonal antibody SCLC 5023 reacted with tumor cell infiltrates in biopsies from small cell lung carcinoma patients (14 of 14 cases positive), using the immunoperoxidase technique. This monoclonal reagent also reacted with other lung tumor cell types, including atypical carcinoid (5 of 5 positive), epidermoid (4 of 6 positive), undifferentiated and bronchoalveolar (3 of 4 cases each positive) carcinomas. By contrast, monoclonal antibody SCLC 2051 apparently identified an antigen expressed preferentially on small cell lung carcinoma cells (12 of 14 positive) and only rarely reacted with other lung tumor cell types (2 of 34 positive). Both monoclonal antibodies were negative to colon carcinoma, epidermoid carcinoma of the floor of the mouth, breast adenocarcinoma, and B- and T-cell leukemia and lymphoma cells, as determined by the enzyme-linked immunosorbent assay, indirect immunofluorescence, and immunoperoxidase techniques. These observations suggest that SCLC 2051 and SCLC 5023 may be of value in identifying tumor-associated antigens expressed in small cell and other lung carcinomas. In addition, the generation of antibody-producing cells towards common tumor-associated antigens may be enhanced by immunization with multiple tumor cell lines of the same histological type.
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PMID:Characterization of two human small cell lung carcinoma-reactive monoclonal antibodies generated by a novel immunization approach. 620 11

Eight patients with small cell bronchogenic carcinoma treated with intensive combination chemotherapy, with and without radiotherapy, have been followed for a minimum of two and a half years without relapse. One patient, after a prodrome of macrocytic sideroblastic anemia, leukopenia, and thrombocytopenia, experienced erythroleukemia 34 months after starting chemotherapy, and cytogenetic studies revealed extensive chromosomal abnormalities. Another patient had persistent macrocytic anemia and pancytopenia two years after cessation of therapy. The remaining six patients had normal peripheral blood smears and cell counts. A significant incidence of preleukemia syndromes and acute leukemia appearing as late complications in intensively treated small cell lung cancer patients requires confirmation in larger series of long-term survivors. Prospective determination of marrow karyotype abnormalities may help to identify patients at greatest risk for developing secondary leukemia.
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PMID:Erythroleukemia and other hematologic complications of intensive therapy in long-term survivors of small cell lung cancer. 627 4

CLM developed in 60 of 526 patients (11%) with SCLC seen at the NCI between August 1969 and June 1980. Life table analysis revealed an overall 25% risk of CLM at 3 years. CLM was diagnosed during all phases of the patients' clinical course, but the majority (83%) were cases diagnosed at the time of progressive systemic disease. Univariate log rank analysis indicated that pretreatment factors associated with the development of CLM included: involvement of the brain, spinal cord, bone marrow, liver or bone; extensive disease; and male sex. Patients who did not obtain a complete response to systemic therapy were at greater risk of developing CLM than complete responders. Multivariate analysis of these factors indicated that liver metastases were most strongly associated with the time to development of CLM, followed in order of importance by bone and CNS metastases. Patients usually presented with signs and symptoms reflecting involvement of multiple areas of the neuraxis including the cerebrum, cranial nerves and spinal cord; 51 of the 60 patients had intracerebral metastases and 27 had spinal cord lesions during their clinical course. Autopsy features including focal or diffuse involvement of the leptomeninges with infiltration of the Virchow-Robin spaces were similar to meningeal lymphoma and leukemia, except that CLM was rarely the sole manifestation of CNS tumor. Median survival following the diagnosis of CLM was 7 weeks. However, most deaths were attributed to systemic disease, and treatment with intrathecal chemotherapy and irradiation often provided palliation. With the increased awareness of this complication, an antemortem diagnosis increased from 39% prior to 1977, to 88% of patients after 1977.
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PMID:Carcinomatous leptomeningitis in small cell lung cancer: a clinicopathologic review of the National Cancer Institute experience. 627 48


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