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)

Methoxymorpholinyl doxorubicin (MMDX; PNU 152243) is a promising doxorubicin derivative currently undergoing clinical evaluation. Previous in vitro studies suggested that the compound undergoes hepatic biotransformation by cytochrome P450 (CYP) 3A into a more cytotoxic metabolite(s). The present study examined the role of CYP3A-mediated metabolism in the in vivo antitumor activity and host toxicity of MMDX in the mouse model and investigated the potential for increasing the therapeutic effectiveness of the drug by inducing its hepatic CYP-catalyzed activation. We found that MMDX cytotoxicity for cultured M5076 tumor cells was potentiated 22-fold by preincubating the drug with NADPH-supplemented liver microsomes from untreated C57BL/6 female mice. A greater (50-fold) potentiation of MMDX cytotoxicity was observed after its preincubation with liver microsomes isolated from animals pretreated with the prototypical CYP3A inducer pregnenolone-16alpha-carbonitrile. In contrast, in vivo administration of the selective CYP3A inhibitor troleandomycin (TAO) reduced both potentiation of MMDX cytotoxicity and the rate of CYP3A-catalyzed N-demethylation of erythromycin by isolated liver microsomes (55.5 and 49% reduction, respectively). In vivo antitumor activity experiments revealed that TAO completely suppressed the ability of 90 microg/kg MMDX i.v., a dose close to the LD10, to delay growth of s.c. M5076 tumors in C57BL/6 mice and to prolong survival of DBA/2 mice with disseminated L1210 leukemia. Moreover, TAO administration markedly inhibited the therapeutic efficacy of 90 microg/kg MMDX i.v. in mice bearing experimental M5076 liver metastases; a complete loss of MMDX activity was observed in liver metastases-bearing animals receiving 40 microg/kg MMDX i.v. plus TAO. However, pregnenolone-16alpha-carbonitrile pretreatment failed to enhance MMDX activity in mice bearing either s.c. M5076 tumors or experimental M5076 liver metastases. Additional experiments carried out in healthy C57BL/6 mice showed that TAO markedly inhibited MMDX-induced myelosuppression and protected the animals against lethal doses of MMDX. Taken together, these findings demonstrate that an active metabolite(s) of MMDX synthesized via CYP3A contributes significantly to its in vivo antitumor activity and host toxicity.
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PMID:In vivo antitumor activity and host toxicity of methoxymorpholinyl doxorubicin: role of cytochrome P450 3A. 1086 16

A major goal in tumor immunotherapy consists of breaking potential tumor-specific T-cell unresponsiveness (tolerance), which may explain tumor growth in cancer patients. We report that immunological tolerance to a tumor-associated viral superantigen (SAg) is overcome in a mouse lymphoma model by transfer of allogeneic T cells expressing SAg-reactive Vbeta6 T-cell receptor chains. Surprisingly, upon contact with SAg-expressing lymphoma cells, Vbeta6 T cells became activated rather than tolerized (as reported previously). They also developed SAg-specific cytotoxic T-lymphocyte activity and secreted IL-2 and IFN-gamma. The grafted T cells infiltrated liver metastases, formed close contact with SAg-expressing tumor cells, and caused significant graft-vs. -leukemia (GvL) effects. Selection for tumor resistance among the progeny from a cross between SAg-negative donor and SAg- positive recipient strains revealed a strict correlation between loss of the endogenous SAg tolerogen, rescue of Vbeta6 T cells from SAg-mediated deletion, and leukemia resistance. These findings suggest that immune responses to SAg can be exploited to break tolerance and augment immune responses to tumors.
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PMID:Breaking tolerance to a tumor-associated viral superantigen as a basis for graft-versus-leukemia reactivity. 1092 64

Unconventional treatments are commonly considered by the scientific community to have unproven efficacy but at least no toxicity. Here we report on the case of a breast cancer patient with lung and liver metastases who developed acute myeloid leukemia after treatment with Di Bella multitherapy, leading rapidly to death due to cerebral hemorrhage. Although an increased susceptibility to malignancy could not be excluded, we considered the possible etiologic role of the treatment received. The drug most likely to be associated with the development of leukemia was the cyclophosphamide contained in the Di Bella multitherapy regimen at a dose of 50 mg daily. The clinical features of this leukemia were therefore compared with those expected for secondary leukemia related to alkylating agents. A preceding myelodysplastic phase and the development of the leukemia after the intake of a cumulative cyclophosphamide dose of 15 g were typical chacteristics of secondary leukemia, but the interval between the start of therapy and the onset of leukemia was only 10 months. We conclude that long-term low-dose cyclophosphamide may have leukemogenic potential and the latency period may be shorter than that commonly reported.
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PMID:Acute myeloid leukemia following chronic low-dose cyclophosphamide for metastatic breast cancer. 1140 Dec 5

Drug resistance is often a limiting factor in successful chemotherapy. Our laboratory has been interested in studying mechanisms of resistance to drugs that are targeted to the thymidylate biosynthesis pathway especially those that target thymidylate synthase (TS) and dihydrofolate reductase (DHFR). We have used leukemia as a model system to study resistance to methotrexate (MTX) and colorectal cancer as the model system to study 5-fluorouracil (5-FU) resistance. In leukemias, we and others have shown that transport, efflux, polyglutamylation and hydrolase activities are major determinants of MTX resistance. We have further reported that some leukemic cells have an increase in DHFR gene copy number possibly contributing to the resistant phenotype. Recently, we have begun to study in detail the molecular mechanisms that govern translational regulation of DHFR in response to MTX as an additional resistance mechanism. Studies thus far involving colorectal tumors obtained from patients have focused predominantly on the predictive value of levels of TS expression and p53 mutations in determining response to 5-FU. Although the predictive value of these two measures appears to be significant, given the variety of resistance to 5-FU observed in cell lines, it is not likely that these are the only measures predictive of response or responsible for acquired resistance to this drug. The enzyme uridine-cytidine monophosphate kinase (UMPK) is an essential and rate-limiting enzyme in 5-FU activation while dihydropyrimidine dehydrogenase (DPD) is a catabolic enzyme that inactivates 5-FU. Alterations in UMPK and DPD may therefore explain failure of 5-FU response in the absence of alterations in TS or p53. Transcription factors that regulate TS may also influence drug sensitivity. We have found that mRNA levels of the E2F family of transcription factors correlates with TS message levels and are higher in lung metastases than in liver metastases of colorectal cancers. Moreover, gene copy number of the E2F-1 gene appears to be increased in a significant number of samples obtained from metastases of colorectal cancer. We have also generated mutants of both DHFR and TS that confer resistance to MTX as well as 5-FU by random as well as site-directed mutagenesis. These mutants used alone or as fusion cDNAs of the mutants have proven to be useful in transplant studies where transfer of these mutant cDNAs to bone marrow cells have been shown to confer drug resistance to recipients. The fusion cDNAs of DHFR such as the DHFR-herpes simplex virus type 1 thymidine kinase (HSVTK) are also useful for regulation of gene expression in vivo using MTX as the small molecule regulator that can be monitored by positron emission tomography (PET) scanning or by optical imaging using a fusion construct such as DHFR-EGFP.
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PMID:Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. 1208 58

In the early 1990s gene therapy had the promise of a new therapeutic modality for many types of cancer including colorectal liver metastases. At the end of that decade the outlook was less encouraging following the death of a patient receiving adenovirus in Pennsylvania. Today the prospect is very bleak following the discovery of leukaemia in children treated for SCiD syndrome in France. Does this mean the start and fall of gene therapy? In this article the concept of gene therapy for colorectal liver metastases will be reviewed. Studies in this field will be cited. It is clear that there are several obstacles to surmount. It is difficult to foresee whether gene therapy will succeed in the clinics in patients with colorectal liver metastases. In this article the author will describe the systematic approach which might lead to success of gene therapy in these patients. In short, gene therapy so far has failed in patients with colorectal liver metastases. However it might succeed in the future. The jury is still out!
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PMID:[Gene therapy in the treatment of colorectal cancer liver metastases]. 1497 54

The use of hepatic arterial infusion (HAI) chemotherapy in patients with liver-only colorectal metastases is based on the pharmacologic principle that the regional administration of some drugs can lead to higher drug concentrations at the site of the metastases and avoid systemic toxicity. Early randomized trials resulted in high response rates but did not lead to a survival advantage with HAI. More recent trials have utilized improved surgical techniques and strict guidelines regarding dose reduction or cessation of HAI chemotherapy, resulting in a significant reduction in toxicity. In patients with unresectable liver metastases, two recent European trials using HAI fluorouracil (5-FU) again failed to demonstrate an improvement in survival, but both were plagued by a high complication rate with an associated high proportion of patients failing to receive the assigned treatment. In contrast, the preliminary results of a recent Cancer and Leukemia Group B trial did demonstrate a survival advantage with HAI floxuridine when compared to systemically administered 5-FU. Trials investigating the use of HAI chemotherapy in the adjuvant setting have yielded mixed results. Moreover, in light of improved response rates and overall survival with newer more active chemotherapeutic and novel agents, the absolute role of HAI chemotherapy remains undefined.
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PMID:Defining the role of hepatic arterial infusion chemotherapy in metastatic colorectal cancer. 1521 95

Judging from recent data, heritable forms account for 30-40% of pheochromocytomas. The molecular basis for the familial pheochromocytoma has been largely elucidated and the role of germline mutation of the VHL, RET, SDHB, and SDHD genes has been established. However, on genotyping a group of 172 sporadic or familial pheochromocytomas, we characterized four unrelated probands with familial pheochromocytomas without any sequence variants of RET (exons 8, 10, 11, 13, 14, 15, and 16) or the entire coding sequence of VHL, SDHB, SDHC, SDHD, and EGLN3 (exon-intron boundaries included). The proband of family 1 is a man who had a bilateral pheochromocytoma at the age of 32 and a local recurrence at the age of 48 years. His brother died of malignant pheochromocytoma and his nephew died suddenly of an undiagnosed pheochromocytoma. The proband of family 2 is a female who had a 5-cm benign adrenal pheochromocytoma at the age of 34 years, while her cousin (maternal branch) had a monolateral pheochromocytoma at the age of 42 years. No other tumors had been reported in either family. The proband of family 3 is a female who had a bilateral pheochromocytoma at the age of 66 years. Her sister had a bilateral pheochromocytoma and breast cancer at the age of 54 years. Several other tumors were recorded in this family, including laryngeal cancer, leukemia, and a case of medullary thyroid carcinoma (MTC) in one brother. MTC was naturally ruled out in the proband and her sister. In family 4, the proband was a female who had a bilateral pheochromocytoma at the age of 46 years and a local recurrence a few years later, with liver metastases from the pheochromocytoma. Her brother had a monolateral benign pheochromocytoma. The proband also had a melanoma and bilateral renal cysts. This case revealed a VHL sequence variant IVS2+43 A>G, which was also found in one other unrelated sporadic pheochromocytoma. VHL mRNA integrity is currently being evaluated. The proband had no cerebellar or spinal NMR findings or retinal alterations. In family 5, the proband was a female who had a right adrenal pheochromocytoma at the age of 50 years and a breast cancer at 49 years of age. Her mother had had a right adrenal pheochromocytoma at 61 years of age. Although other molecular mechanisms, such as particular variants in untranslated regions or partial gene deletions, cannot be ruled out, we think finding families with nonsyndromic pheochromocytoma without any RET, VHL, SDHB, SDHC, SDHD, or EGLN3 mutation may argue in favor of the presence of other pheochromocytoma susceptibility genes.
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PMID:Familial nonsyndromic pheochromocytoma. 1710 81

A cellular cancer therapy is described with unique efficiency even in late-stage disease. in situ activated tumor-immune T cells, induced in allogeneic, tumor-resistant, MHC identical but superantigen different donor mice (B10.D2) could transfer strong graft-versus-leukemia (GvL) effects accompanied by only mild graft-versus-host (GvH) reactivity. Systemic immune cell transfer into 5 Gy irradiated DBA/2 mice bearing up to 4 week established syngeneic tumors and macrometastases led to massive infiltration of tumor tissues by CD4 and CD8 donor T lymphocytes. Upon interaction of immune CD4 donor T cells with host antigen presenting cells in synergy with immune CD8 donor T cells attacking the tumor cells directly, primary tumors (1.5 cm diameter) were encapsulated and rejected from the skin and liver metastases eradicated. For the first time, such adoptive cellular immunotherapy (ADI) was followed in individual live animals by P-31-NMR spectroscopy of primary tumors. An approximately 25,000 fold excess of metastatic tumor cells could be rejected as revealed quantitatively by FACScan analysis of lacZ gene transfected tumor cells.
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PMID:Effective immune rejection of advanced metastasized cancer. 2155 65

A 51-year-old woman diagnosed as having left breast cancer with axillary lymph node and liver metastases seven years earlier was seen in our office because of severe pancytopenia. She had received chemotherapy including several cycles of doxorubicin plus cyclophosphamide and docetaxel followed by hormone therapy containing leuprorelin and tamoxifen over four years. For management of bone pain due to metastasis, she had also undergone stereotaxic radiation therapy of the neck one and a half years earlier and unsealed internal radiation therapy with (89)Sr injection five months prior to the current presentation, Subsequently, myelosuppression progressively worsened and she finally required a blood transfusion. Although bone marrow examination showed severe hypoplasia, but neither blastic nor dysplastic, a test for PML-RARA fluorescence in situ hybridization was positive. After administration of all-trans retinoic acid, hematogenesis improved within three weeks. Neither disseminated intravascular coagulation nor retinoic acid syndrome was observed during the course of her illness. This is the first report describing acute promyelocytic leukemia after administration of (89)Sr, to our knowledge, and with an atypical onset and progression. As the number of cancer survivors increases due to improvements in medical intervention, clinicians must take more notice of special characteristics of therapy-related leukemia modified by previous treatments.
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PMID:[Atypical onset of therapy-related acute promyelocytic leukemia after combined modality therapy including (89)Sr for metastatic breast cancer]. 2400 36


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