Purpose:
A phase 1 study was initiated to determine the safety, potential effectiveness, and maximal tolerated dose and recommended phase 2 dose of efatutazone and paclitaxel in anaplastic thyroid ...cancer.
Experimental Design:
Patients received efatutazone (0.15, 0.3, or 0.5 mg) orally twice daily and then paclitaxel every 3 weeks. Patient tolerance and outcomes were assessed, as were serum efatutazone pharmacokinetics.
Results:
Ten of 15 patients were women. Median age was 59 years. Seven patients received 0.15 mg of efatutazone, 6 patients received 0.3 mg, and 2 patients received 0.5 mg. One patient receiving 0.3 mg of efatutazone had a partial response from day 69 to day 175; 7 patients attained stable disease. Median times to progression were 48 and 68 days in patients receiving 0.15 mg of efatutazone and 0.3 mg of efatutazone, respectively; corresponding median survival was 98 vs 138 days. The median peak efatutazone blood level was 8.6 ng/mL for 0.15-mg dosing vs 22.0 ng/mL for 0.3-mg twice daily dosing. Ten patients had grade 3 or greater adverse events (Common Terminology Criteria for Adverse Events), with 2 of these (anemia and edema) related to efatutazone. Thirteen events of edema were reported in 8 patients, with 2 of grade 3 or greater. Eight patients had ≥1 serious adverse event, with 1 of these (anemia) attributed to efatutazone and 1 (anaphylactic reaction) related to paclitaxel. The maximal tolerated dose was not achieved. Angiopoietin-like 4 was induced by efatutazone in tissue biopsy samples of 2 patients.
Conclusions:
Efatutazone and paclitaxel in combination were safe and tolerated and had biologic activity.
We previously reported that chaetocin has potent and selective anti-myeloma activity attributable to reactive oxygen species (ROS) induction imposed by inhibition of the redox enzyme thioredoxin ...reductase; we now detail its effects in solid tumours.
Cellular assays, transcriptional profiling and the NCI60 screen were used to assess the effects of chaetocin in solid tumour and endothelial cells.
NCI-60 screening demonstrated chaetocin to even more potently inhibit proliferation in solid tumour than in haematological cell lines; transcriptional profiling revealed a signature consistent with induction of inflammatory response and cell death pathways. Chaetocin induced ROS, oxidative damage to cellular proteins and apoptosis, with 2-10 nM IC(50)s (24 h exposures) in all tested solid tumour cell lines. The pan-caspase inhibitor zVAD-fmk did not block chaetocin-induced cell death despite inhibiting mitochondrial membrane depolarisation and apoptosis. Further, Molt-4 rho(0) cells lacking metabolically functional mitochondria were readily killed by chaetocin; in addition chaetocin-induced cytotoxicity was unaffected by autophagy inhibitors or hypoxia and consequent HIF-1α upregulation. Moreover, chaetocin inhibited SKOV3 ovarian cancer xenografts producing less vascular tumours, and inhibited human umbilical vein endothelial cell proliferation.
Chaetocin has intriguing and wide-ranging in vitro and in vivo anticancer effects, and is an attractive candidate for further preclinical and clinical development.
Flavopiridol, the first potent cyclin-dependent kinase inhibitor to undergo clinical trials as an antineoplastic agent in the United States, has attracted considerable attention because of its unique ...cellular targets and its ability to kill noncycling tumor cells in vitro. To better understand how flavopiridol might be used clinically, the present study used colony-forming assays to examine the cytotoxicity resulting from combining flavopiridol with eight other antineoplastic agents in four different administration schedules in A549 human non-small cell lung carcinoma cells in vitro. Cytotoxic synergy, as assessed by the median effect method, resulted when flavopiridol was combined with seven of the eight tested antineoplastic agents but was highly dependent upon administration schedule. Cisplatin was the only agent that resulted in sequence-independent synergy when combined with flavopiridol. For paclitaxel, cytarabine, topotecan, doxorubicin, and etoposide, synergy was more pronounced when the agents were administered before flavopiridol rather than concomitant with or following flavopiridol. Examination suggested that this sequence dependence reflected arrest of cells in G1 and G2 phases of the cell cycle during and for 24 h following flavopiridol treatment. Interestingly, 48-72 h after flavopiridol removal, the fraction of surviving cells in S phase increased 2-3-fold relative to untreated controls. Consistent with these results, administration of flavopiridol for 24 h followed 3 days later by exposure to an S phase-active agent (cytarabine or 5-fluorouracil) resulted in a highly synergistic interaction. These results highlight the importance of administration schedule when combining flavopiridol with other agents and provide a starting point for examining the effect of flavopiridol in drug combinations in vivo.
Flavopiridol binds to duplex DNA BIBLE, K. C; BIBLE, R. H; KOTTKE, T. J ...
Cancer research (Chicago, Ill.),
05/2000, Letnik:
60, Številka:
9
Journal Article
Recenzirano
Flavopiridol, the first potent cyclin-dependent kinase inhibitor to enter clinical trials, was recently found to be cytotoxic to noncycling cells. The present studies were performed to examine the ...hypothesis that flavopiridol, like several other antineoplastic agents that kill noncycling cells, might also interact with DNA. Consistent with this possibility, treatment of A549 human lung cancer cells with clinically achievable concentrations of flavopiridol resulted in rapid elevations of the DNA damage-responsive protein p53. In further studies, the binding of flavopiridol to DNA was examined in vitro by four independent techniques. Absorption spectroscopy revealed that addition of DNA to aqueous flavopiridol solutions resulted in a red shift of the flavopiridol lambda(max) from 311 to 344 nm, demonstrating an isosbestic point typical of changes seen with DNA-binding compounds. Reverse-phase high-performance liquid chromatography demonstrated that flavopiridol binds to genomic DNA to a similar extent as ethidium bromide and Hoechst 33258. Nuclear magnetic resonance spectroscopy revealed that DNA caused extreme broadening of flavopiridol 1H nuclear magnetic resonance signals that could be reversed by addition of ethidium bromide or by DNA melting, suggesting that flavopiridol binds to (and likely intercalates into) duplex DNA. Equilibrium dialysis demonstrated that the equilibrium dissociation constant of the flavopiridol-DNA complex (5.4+/-3.4 x 10(-4) M) was in the same range observed for binding of the intercalators doxorubicin and pyrazoloacridine to DNA. Molecular modeling confirmed the feasibility of flavopiridol intercalation into DNA and analysis of the effects of flavopiridol in the National Cancer Institute tumor cell line panel using the COMPARE algorithm demonstrated that flavopiridol most closely resembles cytotoxic antineoplastic intercalators. Collectively, these data suggest that DNA might be a second target of flavopiridol, providing a potential explanation for the ability of this agent to kill noncycling cancer cells.
Because the activities of HER family members are elevated and/or aberrant in a variety of human neoplasms, these cell surface receptors are receiving increasing attention as potential therapeutic ...targets. In the present study, we examined the effect of combining the HER family tyrosine kinase inhibitor CI1033 (PD 183805) with the topoisomerase (topo) I poison 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, in a number of different cell lines. Colony-forming assays revealed that the antiproliferative effects of simultaneous treatment with CI1033 and SN-38 were synergistic in T98G glioblastoma cells and HCT8 colorectal carcinoma cells, whereas sequential treatments were additive at best. In additional studies examining the mechanistic basis for these findings in T98G cells, immunoblotting revealed that the inhibitory effects of CI1033 on epidermal growth factor receptor autophosphorylation were unaffected by SN-38. Likewise, CI1033 had no effect on topo I polypeptide levels, localization, or activity. Nonetheless, CI1033 markedly enhanced the number of covalent topo I-DNA complexes stabilized by SN-38 or the related agent topotecan (TPT). Analysis of intracellular SN-38 levels by high-performance liquid chromatography and intracellular TPT levels by flow microfluorometry revealed that CI1033 increased the steady-state accumulation of SN-38 and TPT by 9.4 +/- 1.9- and 1.8 +/- 0.2-fold, respectively. Further evaluation revealed that the initial rate of TPT uptake was unaffected by CI1033, whereas the rate of efflux was markedly diminished. Additional studies demonstrated that T98G and HCT8 cells express the breast cancer resistance protein (BCRP), a recently cloned ATP binding cassette transporter. Moreover, CI1033 enhanced the uptake and cytotoxicity of SN-38 and TPT in cells transfected with BCRP but not empty vector. Conversely, CI1033 accumulation was diminished in cells expressing BCRP, suggesting that CI1033 is a substrate for this efflux pump. These results indicate that CI1033 can modulate the accumulation and subsequent cytotoxicity of two widely used topo I poisons in cells that have no history of previous exposure to these agents.
Flavopiridol (NSC 649890, L86-8275), a potent inhibitor of cyclin-dependent kinase 1/p34cdc2 phosphorylation and kinase activity, is currently undergoing Phase I clinical testing as a potential ...antineoplastic agent. Previous studies have suggested that flavopiridol is cytostatic but not cytotoxic when applied to exponentially growing cells. In the present study, various human tumor cell lines were assayed for trypan blue exclusion and ability to form colonies after exposure to flavopiridol under a variety of growth conditions. When log phase A549 non-small cell lung cancer cells were examined 72 h after the start of a 24-h flavopiridol exposure, as many as 90% of the cells accumulated trypan blue. A 24-h exposure to 250-300 nM resulted in trypan blue uptake in 50% of A549 cells at 72 h and a 50% reduction in colony formation. Similar results were observed in HCT8 ileocecal adenocarcinoma, T98G glioblastoma, MCF-7 breast adenocarcinoma, and HL-60 leukemia cells. With A549 cells, identical results were obtained in actively growing logarithmic phase cells and growth-arrested confluent cells. Treatment with the DNA synthesis inhibitor aphidicolin only minimally affected the cytotoxicity of flavopiridol. In contrast, the RNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole or the protein synthesis inhibitor cycloheximide reduced the cytotoxicity of flavopiridol. These results suggest that: (a) flavopiridol is not only cytostatic, but also cytotoxic to a variety of human tumor cell lines; (b) flavopiridol is equally active against cycling and noncycling A549 cells; and (c) RNA and protein synthesis appear to play a role in flavopiridol-induced cytotoxicity.
Differential display-PCR between ovarian tumor cell lines and short-term cultures of normal ovarian epithelial cell brushings was used to isolate a differentially expressed transcript and its ...corresponding gene. The gene, which mapped to 13q14.1, has partial homology in the DNAJ domain to a number of proteins with a similar domain and was designated as methylation-controlled J protein (MCJ). MCJ has the highest similarity to a functionally undefined protein from Caenorhabditis elegans. MCJ is expressed as a 1.2-kb transcript in several adult tissues, with testis showing the highest level of expression. Expression of MCJ was absent in three of seven ovarian cancer cell lines. Similarly, expression analysis using semiquantitative reverse transcription-PCR indicated that 12 of 18 primary ovarian tumors examined had either a complete absence or lower levels of expression of this gene. 5-Aza-2'-deoxycytidine treatment of the OV202 cell line induced MCJ expression in a dose-dependent manner, implicating methylation in this induction. Loss of heterozygosity and methylation-specific PCR analysis revealed that the loss of MCJ expression in primary tumors and cell lines was attributable to deletion of one allele and methylation of the other. To assess the potential functional significance of MCJ down-regulation, the sensitivity of parental (MCJ-nonexpressing) and MCJ-transfected OV167 cells to antineoplastic agents was evaluated. MCJ expression was associated with enhanced sensitivity to paclitaxel, topotecan, and cisplatin, suggesting that MCJ loss may play a role in de novo chemoresistance in ovarian carcinoma. These observations raise the possibility that MCJ loss may: (a) have potential prognostic significance in ovarian cancer; and (b) contribute to the malignant phenotype by conferring resistance to the most commonly used chemotherapeutic agents for ovarian cancer.
Большой прогресс в лечении распространенного медуллярного рака щитовидной железы за последние 5 лет достигнут благодаря одобрению 2 препаратов – вандетаниба и кабозантиниба. Действие этих ингибиторов ...протеинкиназ во многом совпадает и направлено на различные мишени, участвующие в патогенезе медуллярного рака щитовидной железы. Оба препарата имеют достаточно широкий ряд токсических побочных эффектов, таких как артериальная гипертензия, кровотечения, перфорация кишечника, диарея и другие нежелательные явления со стороны желудочно-кишечного тракта, поражения кожи и гипотиреоз. Кроме того, вандетаниб может вызывать удлинение интервала QT из-за взаимодействия с калиевыми ионными каналами клеток миокарда, а кабозантиниб – ладонно-подошвенный синдром. Связанные с лечением токсические эффекты возникают достаточно часто, могут быть очень тяжелыми и даже опасными для жизни. Следовательно, пациенты, получающие эти препараты в течение длительного времени, имеют весьма высокий риск развития побочных эффектов. В данной статье даны практические рекомендации по лечению побочных эффектов применения вандетаниба и кабозантиниба. Рекомендуемый нами подход основан на раннем выявлении побочных эффектов и их своевременном лечении на фоне прерывания терапии ингибиторами протеинкиназ или снижения их дозы, чтобы обеспечить как можно более длительное применение максимально допустимой для конкретного пациента дозы препарата и предотвратить ухудшение качества его жизни. На сегодняшний день отсутствуют рекомендации по выбору очередности применения вандетаниба и кабозантиниба, однако большинство пациентов получают оба эти препарата. Выбор терапии 1-й линии следует проводить в индивидуальном порядке после тщательной оценки потенциальных рисков и пользы. Часто этот выбор зависит от предпочтений врача и особенностей пациента, например наличия сопутствующих заболеваний. Поскольку многие специалисты могут быть незнакомы с тонкостями применения таких препаратов, как вандетаниб и кабозантиниб, мы рекомендуем проводить лечение пациентов с медуллярным раком щитовидной железы под контролем опытного, хорошо осведомленного специалиста, а также мультидисциплинарной бригады врачей.
VB-111 is an engineered antiangiogenic adenovirus that expresses Fas-c in angiogenic blood vessels and has previously been shown to have significant antitumor activity in vitro and in vivo in Lewis ...lung carcinoma, melanoma, and glioblastoma models. To evaluate the efficacy of VB-111 in thyroid cancer, we conducted in vivo xenograft nude mouse studies using multiple thyroid cancer-derived cell lines models. VB-111 treatment resulted in 26.6% (P = 0.0596), 34.4% (P = 0.0046), and 37.6% (P = 0.0249) inhibition of tumor growth in follicular, papillary and anaplastic thyroid cancer models, respectively. No toxicity was observed in any model. All tumor types showed a consistent and significant reduction of CD-31 staining (P < 0.05), reflecting a reduction of angiogenic activity in the tumors, consistent with the intended targeting of the virus. A phase 2 clinical trial of VB-111 in patients with advanced differentiated thyroid cancer is ongoing.
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