Approaches to optimal dosing of hexamethylene bisacetamide

@article{Conley2004ApproachesTO,
  title={Approaches to optimal dosing of hexamethylene bisacetamide},
  author={Barbara A. Conley and Merrill J. Egorin and Victoria J. Sinibaldi and Gerald F. Sewack and Curtis Kloc and L Roberts and Eleanor G. Zuhowski and Alan Forrest and David A. Van Echo},
  journal={Cancer Chemotherapy and Pharmacology},
  year={2004},
  volume={31},
  pages={37-45}
}
SummaryHMBA is a potent differentiating agent capable of causing>95% morphological differentiation in cell lines in vitro. The induction of differentiation is dependent on both the concentration of and the duration of exposure to HMBA. However, acute toxicities (neurotoxicity and acidosis) have limited the maximal HMBAcss value to <2mm, which is at the lower limit of effective in vitro concentrations. When HMBAcss values have been maintained at 1–2mm, thrombocytopenia has limited the duration… 

Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins.

It is shown that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2-selective BET inhibitors.

HMBA induces cell death and potentiates doxorubicin toxicity in malignant mesothelioma cells

HMBA has therapeutic potential in MM both as a single agent and through potentiation of DOX toxicity, which supports future investigations on the feasibility of intrapleural chemotherapy with this hybrid polar compound.

Enhancement of baicalin by hexamethylene bisacetamide on the induction of apoptosis contributes to simultaneous activation of the intrinsic and extrinsic apoptotic pathways in human leukemia cells.

The novel combination of baicalin and HMBA synergistically inhibited the proliferation of acute myeloid leukemia (AML) cell lines and showed little toxic effect on peripheral blood mononuclear cells from healthy volunteers, raising the possibility that the novel combination may be a promising regimen for the treatment of AML.

Model-based neutrophil-guided dose adaptation in chemotherapy: evaluation of predicted outcome with different types and amounts of information.

This study indicates that for successful model-based dose adaptation clinically, there is no need for drug concentration sampling, and that one extra neutrophil measurement in addition to the pre-treatment value is sufficient to limit severe neutropenia while increasing dose intensity.

Individualised Cancer Chemotherapy: Strategies and Performance of Prospective Studies on Therapeutic Drug Monitoring with Dose Adaptation

It can be concluded that TDM may contribute to improving cancer chemotherapy in terms of patient outcome and survival and should therefore be further investigated.

HMBA is a putative HSP70 activator stimulating HEXIM1 expression that is down-regulated by estrogen

The relevance of therapeutic drug monitoring in plasma and erythrocytes in anti-cancer drug treatment

The aim of the present review is to detail the progress made in predicting what a drug does in the body, i.e., pharmacodynamics including toxicity and plasma and/or red blood cell concentration monitoring, and techniques generally used in anti-cancer drug monitoring are highlighted.

Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents

This poster presents a brief history of the history of cancer drug development in the Netherlands and some of the key companies and institutions that contributed to the development of these drugs.

References

SHOWING 1-10 OF 37 REFERENCES

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

Based on this trial, the maximum tolerated and recommended phase II doses for HMBA administered on this schedule are 33.6 and 24 g/m2/d, respectively, since steady-state HMBA levels at these doses were only approaching the lower limit demonstrated for in vitro differentiating effectiveness.

Phase I trial using adaptive control dosing of hexamethylene bisacetamide (NSC 95580).

Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was administered to patients with refractory malignant tumors to individualize each patient's dose based on a dosing scheme using an adaptive (feedback) control algorithm, which assumed linear clearance for HMBA.

A new group of potent inducers of differentiation in murine erythroleukemia cells.

A group of compounds, polymethylene bisacetamides (acetylated diamines), which are potent inducers of erythroid differentiation in murine eryTHroleukemia cells are identified and introduced through varying numbers of methylenes substantially increased the effectiveness of these compounds.

Induction of differentiation of human promyelocytic leukemia cells (HL60) by metabolites of hexamethylene bisacetamide.

6-acetamidohexanoic acid, when combined with HMBA or NADAH at various concentrations and ratios, enhanced the differentiation of HL60 cells induced by these two compounds, which may provide some insight into the mechanism of HMBA-induced cellular differentiation.

Phase I clinical and pharmacokinetic study of hexamethylene bisacetamide (NSC 95580) administered as a five-day continuous infusion.

Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was tested in patients with refractory, solid tumors and metabolic acidosis and neurotoxicity, consisting of agitation, hallucinations, confusion, and alteration of consciousness, were dose dependent and dose limiting.

Phase I trial of N-methylformamide (NMF, NSC 3051).

The predominant toxicity was a dose-related syndrome of fatigue, malaise, nausea, and anorexia, which was reflected by a decrease in performance status (Karnofsky) in six of ten patients who received doses greater than or equal to 1,500 mg/m2/wk.

Phase I trial and clinical pharmacological evaluation of hexamethylene bisacetamide administration by ten-day continuous intravenous infusion at twenty-eight-day intervals.

The data indicate that plasma HMBA concentrations in excess of 1 mM for 10 days are associated with substantial hematological and central nervous system toxicity, but that the recommended dosage for Phase II studies by the 10-day schedule is 24 g/m2/day.

Studies on the mechanism of action of hexamethylene bisacetamide, a potent inducer of erythroleukemic differentiation.

  • R. Reuben
  • Biology, Chemistry
    Biochimica et biophysica acta
  • 1979

Combination cytotoxic-differentiation therapy of mouse erythroleukemia cells with 5-fluorouracil and hexamethylene bisacetamide.

The combined sequential cytotoxic-differentiation therapy resulting in synergistic cytotoxicity and differentiation may be the basis of a new approach to cancer therapy and may aid in reducing the amounts of chemotherapeutic agents required for effective treatment, while maintaining or even increasing their therapeutic effects.

Distribution, elimination, metabolism and bioavailability of hexamethylenebisacetamide in rats

SummaryHexamethylenebisacetamide (HMBA), an in vitro differentiating agent, was studied for its pharmaco-dynamic actions in animals. Plasma stability, organ distribution, excretion, oral