Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most of the cytotoxic anticancer drugs in current use have been shown to induce apoptosis in susceptible cells. The fact that disparate agents, which interact with different targets, induce cell death with some common features (endonucleolytic cleavage of DNA, changes in chromatin condensation) suggests that cytotoxicity is determined by the ability of the cell to engage this so-called 'programmed' cell death. The mechanism of the coupling of a stimulus (drug-target interaction) to a response (cell death) is not known, but modulation of this coupling may affect the outcome of drug treatment. This review surveys the recent evidence which supports the idea that the drug-target interaction per se is not the sole determinant of cellular sensitivity of cytotoxic drugs. Studies of the signals which might engage apoptosis, the genes which modulate it and the biochemical process of drug-induced apoptosis itself are described, where possible, for glucocorticoids, topoisomerase inhibitors, alkylating agents, antimetabolites and antihormones. It is suggested that identification of the gene products which couple the stimulus to the response, and so determine intrinsic cellular sensitivity (and resistance), will be important targets for new types of drugs. These might then allow responses to occur in the major cancers of man, which are chemoresistant.
Cancer Metastasis Rev 1992 Sep
PMID:Apoptosis induced by anticancer drugs. 132 66

A major goal of cancer therapy research is identification of critical biochemical targets that mediate the ability of effective cancer chemotherapy to kill tumor cells while allowing the maintenance of normal cell function. A candidate for such a target is DNA topoisomerase II, a ubiquitous enzyme that alters three-dimensional conformation of supercoiled DNA. DNA intercalating agents and epipodophyllotoxins stabilize a DNA and topoisomerase II complex. The process of stabilization probably represents the poisoning of an intermediate state in the normal functioning of the enzyme. This stabilized intermediate state can be measured in whole cells using the filter elution method of Kohn to quantify protein-associated DNA cleavage produced when the cells are exposed to intercalators or epipodophyllotoxins. By altering cell populations in quantifiable ways, four factors appear to influence the magnitude of drug-induced, topoisomerase II-mediated DNA cleavage and cytotoxicity: the proliferative state of the cell (proliferating cells are more sensitive than quiescent ones); the cell cycle state (cells pharmacologically recruited into G1-S are more sensitive than asynchronously growing cells); the chromatin conformation (DNA methylation, polyamine depletion, and other chromosomal changes can alter the magnitude of topoisomerase II-mediated effects); the cellular phenotype (in an as yet uncharacterized manner, malignant cells apparently are more sensitive to topoisomerase II-mediated events than normal cells). These data suggest that the biochemical basis of the therapeutic index of drugs such as the intercalating agents or epipodophyllotoxins may be the intrinsic hypersensitivity of the topoisomerase II in malignant cells to poisoning by these drugs.
Cancer Metastasis Rev 1985
PMID:DNA topoisomerase II as a target of antineoplastic drug therapy. 300 May 74

The drug discovery programs of the National Cancer Institute and the pharmaceutical industry recently have provided oncologists with a wide array of new chemotherapeutic agents that have considerable potential for breast cancer treatment. Foremost among these new agents are the taxanes, of which paclitaxel and docetaxel, the only members of this class currently in clinical use, have been associated with impressive response rates in patients with metastatic disease. Importantly, they display some evidence clinically of not being cross-resistant with the anthracyclines. Efforts now are being directed toward optimizing dose and schedule in the metastatic setting while integrating these agents into standard adjuvant regimens. Other agents that have undergone Phase II testing in breast cancer include vinorelbine, edatrexate, and losoxantrone. It remains to be determined, however, whether these drugs possess substantial advantages over other members of their class. Newer compounds, such as pyrazoloacridine, ICI D1694, topoisomerase-I inhibitors, temozolomide, penclomidine, fumagillin (TNP-470), and differentiators like the retinoids, hold substantial promise because of their unique mechanisms of action; however, Phase II testing of these agents is just beginning. Although alternative approaches to treatment, such as gene therapies, monoclonal antibodies, and growth factor inhibitors, are likely to have a positive impact, it is probable that progress will best be made by combining these strategies with chemotherapy. Therefore, continuation of the search for more effective chemotherapeutic agents should remain a high priority.
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PMID:New chemotherapeutic agents for breast cancer. 791 62

Cells from multicellular spheroids are often more resistant than monolayers to drugs and radiation. While explanations for resistance can be based on differences in cell cycle distribution, inability of the drug to penetrate the spheroid, or the presence of hypoxic cells, these mechanisms do not adequately explain resistance to all agents. Small spheroids (containing about 25-50 cells) exposed to ionizing radiation, hyperthermia, photodynamic therapy, or topoisomerase II inhibitors, are more resistant to killing than monolayers; the close three-dimensional contact in spheroids has been implicated in this resistance. Proposed mechanisms for the 'contact effect' include gap junctional 'reciprocity', cell shape mediated changes in (repair-related) gene expression, and alterations in chromatin packaging which influence DNA repair. The consequences of the contact effect are especially important for multifraction exposures. Another form of resistance can be demonstrated during repetitive treatments; 'regrowth resistance' reflects the capacity of spheroid cells to proliferate more efficiently to compensate for cell killing.
Cancer Metastasis Rev 1994 Jun
PMID:Drug and radiation resistance in spheroids: cell contact and kinetics. 792 46

NAD(P)H dependent cytochrome P450's and other haemoproteins under hypoxia, mediate two-electron reduction of a wide range of structurally dissimilar N-oxides to their respective tertiary amines. Metabolic reduction can be utilised, in acute and chronic hypoxia, to convert N-oxides of DNA affinic agents to potent and persistent cytotoxins. In this respect a knowledge of N-oxide bioreduction and the importance of the cationic nature of agents that bind to DNA by intercalation can be combined to rationalise N-oxides as prodrugs of DNA binding agents. The concept is illustrated using the alkylaminoanthraquinones which are a group of cytotoxic agents with DNA binding affinity that is dependent on the cationic nature of these compounds. The actions of the alkylaminoanthraquinones involve drug intercalation into DNA (and double stranded RNA) and inhibition of both DNA and RNA polymerases and topoisomerase Type I and II. A di-N-oxide analogue of mitoxantrone, 1,4-bis([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxyanthracene -9,10- dione (AQ4N) has been shown to possess no intrinsic binding affinity for DNA and has low toxicity. Yet in the absence of air AQ4N can be reduced in vitro to a DNA affinic agent with up to 1000-fold increase in cytotoxic potency. Importantly the reduction product, AQ4, is stable under oxic conditions. Studies in vivo indicate that antitumour activity of AQ4N is manifest under conditions that promote transient hypoxia and/or diminish the oxic tumour fraction. The advantage of utilising the reductive environment of hypoxic tumours to reduce N-oxides is that, unlike conventional bioreductive agents, the resulting products will remain active even if the hypoxia that led to bioactivation is transient or the active compounds, once formed, diffuse away from the hypoxic tumour regions. Furthermore, the DNA affinic nature of the active compounds should ensure their localisation in tumour tissue.
Cancer Metastasis Rev 1993 Jun
PMID:Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent. 837 16

We investigated four mechanisms of intrinsic chemoresistance in a series of 67 human brain tumours including 31 gliomas (one grade I ganglioglioma, nine grade II and 10 grade III astrocytomas, 11 glioblastomas), 13 cerebral metastases, one medulloblastoma, one malignant teratoma, three ependymomas and 18 meningiomas. We studied four genes by northern blotting: multidrug-resistance (MDR 1), glutathione-s transferase (GST pi), dihydrofolate reductase (DHFR), and topoisomerase II (Topo II). The Topo II gene was absent in the normal adult brain (100%) and in 64% of the tumour samples tested. A second gene, GST pi, was found to be overexpressed in 38% of brain tumours. The two other chemoresistance-related genes were occasionally overexpressed in brain tumours (2% for MDR1, 9% for DHFR). Our results provide evidence that chemoresistance is intrinsic to the brain tissue and seems likely to be a multifactorial process.
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PMID:A study of the expression of four chemoresistance-related genes in human primary and metastatic brain tumours. 838 72

The catalytic cycle of topoisomerase II is the target of some of the most successful antitumor agents used today, e.g. etoposide (VP-16), in the treatment of testicular cancer and small-cell lung cancer. The cell kill mediated by topoisomerase II poisons can be antagonized by distinct drug types. Thus, we have demonstrated etoposide antagonism with the type-II anthracycline aclarubicin, the antimalarial drug chloroquine, and the cardioprotective agent ICRF-187. In other setups, combinations of agonist and antagonists have led to high-dose regimens for counteracting drug resistance. Thus, the exploitation of folinic acid rescue for methotrexate toxicity and the use of mesna to protect against cyclophosphamide toxicity have enabled the use of high-dose methotrexate and cyclophosphamide protocols. Using a similar approach, we have studied possible ways to apply antagonists to topoisomerase II poisons. NDF1-hybrid female mice were treated with the various drugs and drug combinations. Lethality (LD10 and LD50 values) was computed by use of the maximum-likelihood method, and the antitumor effect of the drugs was compared in mice inoculated i.p. with either L1210 cells or Ehrlich ascites tumor cells. In addition, the compounds were tested on L1210 cells inoculated intracranially. The toxicity of the various drugs was evaluated by weight and leukocyte counts. ICRF-187 rescues healthy mice from lethal doses of topoisomerase II poisons. In mice the ICRF-187 LD10 was 500 mg/kg. Within a wide non-toxic dose range (50-250 mg/kg) of ICRF-187 we found protection against m-AMSA and etoposide lethality. Thus, the LD10 of etoposide increased from 34 mg/kg for the single agent to 122 mg/kg for its combination with ICRF-187, corresponding to a 3.6-fold etoposide dose escalation. In contrast, ICRF-187 did not protect against lethal doses of the non-topoisomerase II-directed drug paclitaxel. We further investigated the anti-tumor effect of equitoxic schedules in mice inoculated i.p. with L1210 or Ehrlich ascites tumor cells. The L1210-bearing mice appeared to obtain a larger increase in life span from the etoposide and ICRF-187 combination as compared with etoposide alone, whereas this was not the case in mice inoculated with Ehrlich ascites tumor cells. As the hydrophilic ICRF-187 is not expected to cross the blood-brain barrier, in contrast to the lipophilic etoposide, we investigated the effect of the drug combination in mice inoculated intracranially with L1210 cells. We obtained a significant increase in life span in mice treated with ICRF-187 + etoposide as compared with mice treated with an equitoxic dose of etoposide alone. Thus, there appear to be potential routes by which one can benefit from this antagonism. ICRF-187 is a powerful nontoxic protector against the lethality of the topoisomerase II-directed drugs etoposide and m-AMSA in vivo. A brain tumor model demonstrates the superiority of high-dose etoposide treatment with ICRF-187 protection as compared with etoposide treatment alone. This implies that tumors in the brain can be reached by cytotoxic drug doses and that normal tissues can be protected due to differences in drug transport across the blood-brain barrier. ICRF-187 is therefore a promising lead compound for the development of schedules using high-dose topoisomerase II poisons in the treatment of brain tumors and metastases.
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PMID:ICRF-187 rescue in etoposide treatment in vivo. A model targeting high-dose topoisomerase II poisons to CNS tumors. 864 93

We synthesized a potent new antitumor podophyllotoxin derivative (4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin; TOP-53) in our search for a drug that has strong activity against lung cancer and lung metastatic cancer. TOP-53 exhibited twice the inhibitory activity of etoposide (VP-16) against topoisomerase II and induced DNA strand breaks but showed no inhibitory activity against tubulin polymerization. The in vitro cytotoxic activity of TOP-53 assessed as IC50 was 0.016-0.37 microg/ml and 0.26-8.9 microg/ml against marine tumor and human non-small cell lung cancer (NSCLC) cell lines, respectively. TOP-53 exerted significant efficacy equivalent to that of VP-16 on s.c.-implanted murine solid tumors (Colon 26, B16-BL6, and Lewis lung carcinoma) at doses 3-5 times lower than that of VP-16. In human tumor xenografts using NSCLC, TOP-53 was active for four of five tumors, whereas VP-16 was active for two of five tumors. Potent inhibitory activity of TOP-53 was also found against a lung tumor (Lewis lung carcinoma) and four lung metastatic tumors (NL-22 and NL-17 colon cancer, UV2237M fibrosarcoma, and K1735M2 melanoma). TOP-53 appeared to be more active against four of them than VP-16. Thus, TOP-53 is not only active against s.c.-implanted lung cancers but also strongly active against lung localized tumor and metastatic tumors in the lungs. The high selectivity of TOP-53 was attributed to its high distribution into the lung and its persistence. TOP-53 is expected to be highly effective against lung cancer including NSCLC and various lung metastatic tumors in the clinical field.
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PMID:Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. 866 18

The erbB-2 receptor plays an important role in the prognosis of breast cancer and is expressed at high levels in nearly 30% of tumors in breast cancer patients. While evidence accumulates to support the relationship between erbB-2 overexpression and poor overall survival in human breast cancer, understanding of the biological consequence(s) of erbB-2 overexpression remains elusive. The discovery of heregulin has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through the erbB-2/4 receptor. These endpoints of growth, invasiveness, and differentiation have clear implications for the emergence, maintenance, and/or control of malignancy, and represent established endpoints in the assessment of malignant progression in human breast cancer. Preliminary studies in vitro have shown that heregulin induces a biphasic growth effect on cells with erbB-2 overexpression. Interestingly, we observed that expression of heregulin correlates with a more aggressive/invasive, vimentin-positive phenotype in breast cancer cells lines. Therefore, we have postulated that heregulin is involved in breast cancer tumor progression. We have shown that heregulin induces in vitro chemoinvasion and chemotaxis of breast cancer cells as well as growth in an anchorage dependent and independent manner. Interestingly, a heregulin neutralizing antibody inhibits chemotaxis and results in cell growth inhibition and blockade of the invasive phenotype. Strikingly, genetically engineered cells which constitutively express heregulin demonstrate critical phenotypic changes that are associated with a more aggressive phenotype. Specifically, these cells are no longer dependent on estrogen for growth and are resistant to tamoxifen in vitro and in vivo, and moreover these cells metastasize to lymph nodes in athymic nude mice. These tumors appear to have lost bcl-2 expression as compared with the control tumors. In addition, presumably by activation/regulation of topoisomerase II, the heregulin-transfected cells become exquisitely sensitive to doxorubicin and VP-16. Clearly, mechanistic aspects of the erbB-2/4 and heregulin interaction need to be understood from a therapeutic standpoint which could provide additional insights into synergistic treatments for certain patients, or improve treatment regimens for a large number of women. The study of heregulin and its co-expression with erbB-2/4 receptor and the assessment of its involvement in the progression from the in situ stage of breast tumors to the invasive one will additionally increase the relevance of heregulin as a prognostic/diagnostic factor. We believe that our studies provide new insights into breast cancer diagnosis, prognosis, and treatment.
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PMID:The significance of heregulin in breast cancer tumor progression and drug resistance. 882 23

Cytotoxic drugs currently remain as the basis for the chemotherapy of metastatic cancer. Why they fail to kill sufficient tumour cells in the major human solid cancers, such as the carcinomas, is suggested in this review to be due to the inherent inability of these cells to engage apoptosis after drug-induced damage. As a paradigm for drug resistant cancers, the resistance of bladder carcinoma cell lines to DNA damaging drugs is described here in terms of their response to the topoisomerase II poison etoposide. 60%-70% of bladder carcinomas have mutant p53; this can prevent the detection of and response to DNA damage. In vitro studies with a bladder carcinoma cell line containing a wild type p53 showed that it underwent a G1 checkpoint after etoposide, potentially allowing DNA damage repair, as well as apoptosis. In lines with mutant or non-functional p53 there is no checkpoint and no apoptosis. All lines showed constitutive expression of bcl-2 and bcl-XL (the suppressors of apoptosis) with low and non-inducible levels of bax (a promoter of apoptosis). Taken together, this menu of gene expression is more favourable to survival than apoptosis after the imposition of drug-induced DNA damage and may contribute to their inherent drug resistance.
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PMID:Apoptosis and cancer chemotherapy. 895 Apr 79


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