Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new approach to antitumor analog selection was evaluated using in vitro cytotoxicity assays in tumor cells and heart cells. Eight anthracycline antibiotics and five non-anthracycline DNA intercalating agents were separately exposed to human 8226 myeloma cells and neonatal rat heart myocytes in vitro. Survival was measured after six days of culture by the MTT dye method for tumor cells and by ATP content for heart cells. Inhibitory drug concentrations in 50% of cells (IC50) were determined from log-linear dose-response curves for each agent. The IC50 values in the tumor cells ranged from 0.002 micrograms/ml for idarubicin to 3.5 micrograms/ml for the primary metabolite of doxorubicin, doxorubicinol. In contrast, IC50 values for anthracyclines in rat heart cells averaged approximately 357-fold higher than in the tumor cells. The heart cell/tumor IC50 ratio was 114.4 for the parent anthracycline doxorubicin. Compounds with poor cytotoxic selectivity for tumor cells included doxorubicinol, amonafide, amsacrine and bisantrene. Compounds with reduced cardiotoxicity included the anthracyclines daunorubicin (IC50 ratio of 550), esorubicin (IC50 ratio of 1500) and the anthracene derivative mitoxantrone (IC50 ratio of 500). These results show that simultaneous comparisons of cytotoxicity in heart cells and tumor cells can identify agents such as daunorubicin and mitoxantrone which are known to produce less cardiac toxicity in vivo. With further testing, this methodology may be applicable to preclinical screening programs to select active DNA intercalating agents with low cardiotoxic potential.
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PMID:Comparison of cytotoxicity in heart cells and tumor cells exposed to DNA intercalating agents in vitro. 195 48

To date, random anticancer drug screening has proven to be relatively inefficient and non-specific with respect to selecting active compounds for most tumor types (except for leukemia/lymphoma). Although large numbers of compounds from diverse sources were evaluated for many years in the P388 mouse leukemia model, only a few clinically useful drugs have been identified by this in vivo screening method. Thus, there is intense interest in the development of more effective in vitro screening models for new anticancer drugs. In the present paper we have compared the discriminating power for fresh human tumors from patients, human tumor cell lines developed from 11 patients and murine P388 leukemia in tumor colony forming assays as indicators of cytotoxicity for a series of anthracene antitumor agents. Two of a series of 21 novel bisantrene analogs, R6 (N,N1-bis[2-(dimethylamino)ethyl]-9,10-anthracene-bis(methylamine)) and R26 (N,N1-bis(1-ethyl-3-piperidinyl)-9,10-anthracene-bis(methylamine] produced significant cytotoxicity against the 11 human tumor cell lines and were therefore selected for additional in vitro and in vivo studies. R26 was specifically selected for further testing since it had similar in vitro potency as mitoxantrone, but showed no cross-resistance against mitoxantrone-resistant WiDr colon or doxorubicin-resistant 8226 myeloma cell lines. In contrast to the cell line data, only of the 22 fresh human tumors showed significant in vitro sensitivity (i.e. less than 50% survival of tumor colony forming units) to either R6 or R26 tested at high concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro cytotoxicity against fresh human tumors and P388 leukemia predicts the differential in vivo activity of a series of anthracene anticancer drugs. 195 55

Hybridomas which secrete monoclonal antibodies (MAbs) reacting with doxorubicin (DXR), a widely used anthracycline cytotoxic antibiotic, have been obtained by fusing NSO/P3 mouse myeloma cells with spleen cells from BALB/c mice immunized with DXR-BSA conjugate. The best producer among the several clones obtained was expanded and the secreted MAb (MAD2) purified and characterized. MAD2 cross-reacts to varying degrees with anthracycline compounds such as some DXR analogues and derivatives, but does not recognize anthracene and anthraquinone structures, with the exception of weakly reacting Mitoxantrone. MAD2 and the panel of MAbs which are at present being purified may become a tool for studying the relevance of different domains of the anthracyclin molecule in terms of biologic activity.
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PMID:Monoclonal antibodies against doxorubicin. 318 9

9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride (bisantrene) is a new anthracene bishydrazone derivative which was entered into a Phase I clinical trial (one dose weekly for 3 weeks) because it showed significant antitumor activity in a number of animal tumor models and in vitro in the human tumor stem cell assay. When possible, patients were entered into the phase I study if their tumors showed in vitro sensitivity to bisantrene and resistance to standard agents, using a human tumor stem cell assay. Thirty-one patients were treated with bisantrene over a 10-month period, starting at a dose of 70 mg/sq m/week. The appearance of leukopenia determined the dose-limiting toxicity of bisantrene. The maximally tolerated dose appeared to be 200 mg/sq m in that three of five patients tolerated these weekly-for-3-weeks doses while experiencing only mild or moderate leukopenia. In contrast, the 220-mg/sq m dose caused moderate to life-threatening leukopenia after just two weekly doses in four of five patients. Local bisantrene toxicity included mild to severe arm swelling, phlebitis, pain, urticaria, and erythema in 68% of the patients. In general, these toxicities were well tolerated and rapidly reversible, but two patients had severe local swelling for up to 6 months. In this Phase I trial, bisantrene showed clinical antitumor activity against both hematological cancer (i.e., lymphoma and myeloma) and solid tumors (i.e., bladder, lung, and renal cancer and melanoma). Of importance, four of the six responses occurred in patients whose therapy was selected on the basis of in vitro sensitivity to bisantrene using the human tumor stem cell assay. One patient with disseminated melanoma had complete disappearance of an axillary node metastasis (for more than 6 months) while developing a brain metastasis, suggesting that bisantrene does not concentrate in the central nervous system.
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PMID:Phase I clinical investigation of 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] dihydrochloride with correlative in vitro human tumor clonogenic assay. 703 74

The azonafides are a series of anthracene-based DNA intercalators which inhibit tumor cell growth in vitro at low nanomolar concentrations and are not affected by the multidrug resistance phenomenon (MDR). Prior studies have described antitumor efficacy in murine tumor models including L-1210 and P-388 leukemias, and B-16 melanoma. The current results extend these cell line observations to human tumors tested in the NCI panel of 56 cell lines, in freshly isolated tumors tested in colony-forming assays in soft agar and in several animal models. In the NCI panel, the overall mean 50% cell kill (LC50) for the unsubstituted azonafide, AMP-1, was 10(-5.53) M, with some selectivity noted in melanomas (10(-6.22) M). The mean LC50 for the 6-ethoxy substituted analog, AMP-53, was 10(-5.53) M, with some selectivity found in non-small cell lung cancer (10(-5.91)) and renal cell carcinoma (10(-5.84)). In freshly isolated human tumors tested in soft agar, there was marked activity (mean IC50 in microg/ml) for AMP-53 in four cell types: breast cancer (0.09), lung cancer (0.06), renal cell carcinomas (0.06) and multiple myeloma (0.03). These effects were superior to doxorubicin and to several other azonafides, including AMP-1, AMP-104 and the 6-hydroxyethoxy derivative, AMP-115. Compound AMP-1 was shown to be superior to amonafide in the mammary 16C breast cancer model in B6CF31 mice, but it had little activity in Colon-38 nor in M5076 ovarian sarcomas in vivo. Nine azonafides were evaluated in the Lewis lung cancer model in C57/bl mice, but only AMP-53 demonstrated significant efficacy with a treated/control x 100% (T/C) value of 30%. Because AMP-53 demonstrated the greatest breadth of activity, it was then evaluated in several human tumor cell lines growing in mice with severe combined immunodeficiency disease (SCID). Only three tumors were sensitive (T/C<42%), including HL-60 leukemia (T/C=39%), MCF-7 breast cancer (T/C=39%) and A549 non-small cell lung cancer (T/C=37%). Overall, these results demonstrate that the 6-ethoxy substituted azonafide, AMP-53, has consistent (in vitro and in vivo) experimental antitumor activity in human breast and lung cancer, and could be considered for clinical testing in patients with MDR tumors.
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PMID:Preclinical antitumor activity of the azonafide series of anthracene-based DNA intercalators. 1129 Aug 69

Rice protein isolate (RPI) has been reported to reduce the incidence of 7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats. To determine the potential role of phytochemicals associated with the RPI, we studied in vitro antitumor activities of an ether fraction from RPI using human tumor cell lines, including two human breast carcinoma cell lines (MDA-MB-453 and MCF-7) and two myeloma cell lines (RPMI-8226 and IM-9). Concentration-dependent antiproliferative effects of the ether fraction were observed in all cell lines using the standard 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Fraction-induced apoptosis (P < 0.05) was detected in all cell lines, and this was associated with the induction of proapoptotic bax protein and cdk inhibitors (p21) and the suppression of cdk4 and cyclin D1 activity. Liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) with both positive and negative modes was used to analyze the phytochemicals in the ether fraction from RPI. Fifty-seven phytochemicals were identified or characterized by their diagnostic fragmentation patterns and direct comparison with the authentic standards on the basis of electrospray ionization-MS/MS data. The major components bound to RPI were lysoglycerophospholipids, fatty acids, and fatty acid 3-[2-(2,3-dihydroxy-propoxycarbonyl)-2-hydroxy-ethoxy]-2-hydroxy-propyl esters.
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PMID:In vitro actions on human cancer cells and the liquid chromatography-mass spectrometry/mass spectrometry fingerprint of phytochemicals in rice protein isolate. 1675 84

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Although multiple myeloma patients often respond to initial therapy, the majority of patients will relapse with disease that is refractory to further drug treatment. Thus, new therapeutic strategies are needed. One common mechanism of acquired drug resistance involves a reduction in the expression or function of the drug target. We hypothesized that the cytotoxic activity of topoisomerase II (topo II) poisons could be enhanced, and drug resistance overcome, by increasing the expression and activity of the drug target, topo II in myeloma cells. To test this hypothesis, we evaluated the cytotoxicity of the anthracene-containing topo II poison, ethonafide (AMP-53/6-ethoxyazonafide), in combination with the proteasome inhibitor bortezomib (PS-341/Velcade). Combination drug activity studies were done in 8226/S myeloma cells and its drug resistant subclone, 8226/Dox1V. We found that a 24-h treatment of cells with bortezomib maximally increased topo IIalpha protein expression and activity, and consistently increased the cytotoxicity of ethonafide in the 8226/S and 8226/Dox1V cell lines. This increase in cytotoxicity corresponded to an increase in DNA double-strand breaks, as measured by the neutral comet assay. Therefore, increasing topo IIalpha expression through inhibition of proteasomal degradation increased DNA double-strand breaks and enhanced the cytotoxicity of the topo II poison ethonafide. These data suggest that bortezomib-mediated stabilization of topo IIalpha expression may potentiate the cytotoxic activity of topo II poisons and thereby, provide a strategy to circumvent drug resistance.
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PMID:Proteasomal inhibition stabilizes topoisomerase IIalpha protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide). 1806 37