Phase I and pharmacologic study of hexamethylene bisacetamide in patients with advanced cancer.

Rowinsky, Eric K.; Ettinger, David S.; Grochow, Louise B.; Brundrett, Robert B.; Cates, A. E.; Donehower, Ross C.

doi:10.1200/jco.1986.4.12.1835

Cited by 28 publications

(4 citation statements)

References 15 publications

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“…The clinically tested chemotherapeutic hexamethylene bisacetamide (HMBA) [32] has been demonstrated to alleviate this transcriptional block by promoting the localization of P-TEFb to the LTR to enhance viral transcriptional elongation [33–35]. We hypothesized that any drug synergy observed between TNF and HMBA would not show a strong dependence on the chromatin environment of the latent viral integration because P-TEFb levels should be similar across Jurkat cells regardless of the viral integration site.…”

Section: Resultsmentioning

confidence: 99%

Quantitative Evaluation and Optimization of Co-drugging to Improve Anti-HIV Latency Therapy

et al. 2014

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Human immunodeficiency virus 1 (HIV) latency remains a significant obstacle to curing infected patients. One promising therapeutic strategy is to purge the latent cellular reservoir by activating latent HIV with latency-reversing agents (LRAs). In some cases, co-drugging with multiple LRAs is necessary to activate latent infections, but few studies have established quantitative criteria for determining when co-drugging is required. Here we systematically quantified drug interactions between histone deacetylase inhibitors and transcriptional activators of HIV and found that the need for co-drugging is determined by the proximity of latent infections to the chromatin-regulated viral gene activation threshold at the viral promoter. Our results suggest two classes of latent viral integrations: those far from the activation threshold that benefit from co-drugging, and those close to the threshold that are efficiently activated by a single drug. Using a primary T cell model of latency, we further demonstrated that the requirement for co-drugging was donor dependent, suggesting that the host may set the level of repression of latent infections. Finally, we showed that single drug or co-drugging doses could be optimized, via repeat stimulations, to minimize unwanted side effects while maintaining robust viral activation. Our results motivate further study of patient-specific latency-reversing strategies.

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Section: Resultsmentioning

confidence: 99%

Quantitative Evaluation and Optimization of Co-drugging to Improve Anti-HIV Latency Therapy

et al. 2014

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“…Furthermore, experimentation showed that HMBA also induced terminal differentiation in a variety of leukemic cell lines [2, 10]. Based on these findings, HMBA was studied in several Phase I and Phase II clinical trials for the treatment of myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), general advanced cancer, and solid tumors [3-9]. However, serious side effects of HMBA, such as thrombocytopenia, limited the dose escalation and prevented sufficient plasma concentrations to be realized for its terminal differentiating potential.…”

Section: Introductionmentioning

confidence: 99%

“…Up to date, the published analytical methods for the measurement of HMBA in plasma and urine are LC-UV and GC-N/P based methods, which have lower limits of quantitation (LLOQs) of 1.00 μg/mL and 2.00 μg/mL, respectively [17, 18]. These and other methods have been applied to several high-dose HMBA Phase I and II clinical trials [3-9, 19, 20], but the LLOQs of these methods are not sufficient for the measurement of HMBA in the majority of biological samples for breast cancer study with concentrations less than 1.00 μg/mL. This paper describes, for the first time, the development and validation of an LC-MS/MS method for the quantitative measurement of HMBA in both mouse and human plasma with an LLOQ of 0.500 ng/mL and a linear calibration range up to 100 ng/mL.…”

Section: Introductionmentioning

confidence: 99%

Determination of hexamethylene bisacetamide, an antineoplastic compound, in mouse and human plasma by LC–MS/MS

Smith

Ketchart

Zhou

et al. 2011

Journal of Chromatography B

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Hexamethylene bisacetamide (HMBA) is a polar compound which has recently been discovered to have antineoplastic activity by up-regulating the expression of an endogenous antiproliferative breast cancer protein, HEXIM1 (hexamethylene bisacetamide inducible protein 1) in vivo. HMBA has been shown in the past to induce terminal differentiation in multiple leukemia types at a concentration of 2-5 mM, but its phase I and II clinical trials were largely unsuccessful due to serious side effects (notably, thrombocytopenia) with dose escalation. In this work, a sensitive and simple LC-MS/MS method for direct determination of HMBA in mouse and human plasma is described. Plasma samples were prepared by deproteinization with acetonitrile. Separation was achieved on a Waters Atlantis® T3 (2.1 × 50 mm, 3 μm) column with retention times of 2.2 and 3.7 min for HMBA and 7MBA (internal standard), respectively. The quantitation was carried out by tandem mass spectrometry using positive MRM mode. The linear range of the method was 0.500-100 ng/mL in both mouse and human plasma with injection volume of 5 μL. This method has been validated in accordance with the US Food and Drug Administration (FDA) guidelines for bioanalytical method development and applied to the determination of HMBA concentrations in FVB mice over time after a single dose of HMBA in saline (0.9% NaCl) at 10 mg/kg.

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“…The in vitro studies provided a basis for evaluating the potential of HMBA as a cytodifferentiation agent in the treatment of human cancers (26). Several phase I clinical trials with HMBA have been completed (27)(28)(29)(30)(31)(32). Evidence has been reported that this compound can induce a therapeutic response in patients with cancer (31,32).…”

mentioning

confidence: 99%

Polar/apolar chemical inducers of differentiation of transformed cells: strategies to improve therapeutic potential.

Marks

Breslow

Rifkind

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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N,N'-Hexamethylenebisacetamide (HMBA) induces transformed cells to differentiate, accompanied by suppression of oncogenicity. Clinical trials have shown that HMBA can cause positive therapeutic responses in some cancer patients, but clinical efficacy may be limited, in part, by dose-related toxicity. Potential improvements in efficacy may be accomplished by changes in the chemical structure of inducing agents and by increasing the sensitivity of tumor cells to inducers of differentiation. We have previously described an approach to improving tumor cell responsiveness to inducing agents. Transformed cell lines that have acquired low levels of resistance to vincristine display a markedly increased sensitivity to HMBA. We now report on a series of hybrid polar/apolar compounds--some of which are as active as HMBA and several of which are significantly more active than HMBA in vitro--whose chemical structures make it likely that they have different pharmacokinetics. Vincristine-resistant murine erythroleukemia cells also are shown to have marked increased sensitivity to these hybrid polar/apolar compounds. Thus these findings suggest potentially useful strategies for the application of polar/apolar inducers of differentiation to the treatment of cancers. These studies also provide approaches to further understanding of the biological process of terminal differentiation.

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Phase I and pharmacologic study of hexamethylene bisacetamide in patients with advanced cancer.

Cited by 28 publications

References 15 publications

Quantitative Evaluation and Optimization of Co-drugging to Improve Anti-HIV Latency Therapy

Quantitative Evaluation and Optimization of Co-drugging to Improve Anti-HIV Latency Therapy

Determination of hexamethylene bisacetamide, an antineoplastic compound, in mouse and human plasma by LC–MS/MS

Polar/apolar chemical inducers of differentiation of transformed cells: strategies to improve therapeutic potential.

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