Colchicine in refractory chronic lymphocytic leukemia

Weick, James K.; Livingston, Robert B.; Slyck, Ellis J. Van

doi:10.1007/bf00177418

Cited by 5 publications

(2 citation statements)

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“…We have evaluated our initial approach to rational drug design based on tubulin as a target and specifically its colchicine binding site. We have chosen the colchicine site because: 1) colchicine is a drug with a long clinical history [6]; 2) the precise mechanisms of colchicine binding, including conformational effects, have been worked out better than for any other tubulin-binding drug [7-14]; 3) the synthetic chemistry of colchicine and its derivatives is simpler than that of other tubulin-binding drugs [15,16]; 4) colchicine has strong anti-mitotic activity which can be used as a standard for comparison of the derivatives that we design [17]; 5) colchicine has been used in clinical trials but, due to dose-limiting general toxicities has not been successful so far [6]; 6) tubulin isotypes differ significantly from each other in their binding to colchicine and some of its derivatives. Our hope is that by altering the structure of the drug to make it more specific for cancer cells, its therapeutic concentration can be lowered below the toxicity limit.…”

Section: Introductionmentioning

confidence: 99%

Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives

et al. 2010

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BackgroundA maximum entropy approach is proposed to predict the cytotoxic effects of a panel of colchicine derivatives in several human cancer cell lines. Data was obtained from cytotoxicity assays performed with 21 drug molecules from the same family of colchicine compounds and correlate these results with independent tubulin isoform expression measurements for several cancer cell lines. The maximum entropy method is then used in conjunction with computed relative binding energy values for each of the drug molecules against tubulin isotypes to which these compounds bind with different affinities.ResultsWe have found by using our analysis that αβI and αβIII tubulin isoforms are the most important isoforms in establishing predictive response of cancer cell sensitivity to colchicine derivatives. However, since αβI tubulin is widely distributed in the human body, targeting it would lead to severe adverse side effects. Consequently, we have identified tubulin isotype αβIII as the most important molecular target for inhibition of microtubule polymerization and hence cancer cell cytotoxicity. Tubulin isotypes αβI and αβII are concluded to be secondary targets.ConclusionsThe benefit of being able to correlate expression levels of specific tubulin isotypes and the resultant cell death effect is that it will enable us to better understand the origin of drug resistance and hence design optimal structures for the elimination of cancer cells. The conclusion of the study described herein identifies tubulin isotype αβIII as a target for optimized chemotherapy drug design.

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Section: Introductionmentioning

confidence: 99%

Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives

et al. 2010

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“…[5] Although COL and structurally related compounds have therapeutic effects towards various types of cancer, [6][7][8][9][10][11] undesirable side-effects have limited their application, and this has stimulated the development of new therapeutics centered on COL structure. [12] Towards this end, and to decrease toxicity towards normal cells and retain the original activity in the nanomolar range towards cancer cells, a series of new COL derivatives, namely N-carbamates of N-deacetylthiocolchicine and -deacetyl-4-(bromo/chloro/iodo)thiocolchicine, have been previously synthesized. [13][14][15][16] Potent activity for some of these compounds towards A549 lung cancer cells, MCF-7 breast cancer cells, LoVo colon cancer cells, and its doxorubicin-resistant variant, LoVo/DX, has been reported.…”

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Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells—in vitro and ex vivo study

Urbaniak

Jousheghany

Piña‐Oviedo

et al. 2020

J Biochem & Molecular Tox

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Colchicine (COL) shows strong anticancer activity but due to its toxicity towards normal cells its wider application is limited. To address this issue, a library of 17 novel COL derivatives, namely N‐carbamates of N‐deacetyl‐4‐(bromo/chloro/iodo)thiocolchicine, has been tested against two types of primary cancer cells. These included acute lymphoblastic leukemia (ALL) and human breast cancer (BC) derived from two different tumor subtypes, ER+ invasive ductal carcinoma grade III (IDCG3) and metastatic carcinoma (MC). Four novel COL derivatives showed higher anti‐proliferative activity than COL (IC50 = 8.6 nM) towards primary ALL cells in cell viability assays (IC50 range of 1.1‐6.4 nM), and several were more potent towards primary IDCG3 (IC50 range of 0.1 to 10.3 nM) or MC (IC50 range of 2.3‐9.1 nM) compared to COL (IC50 of 11.1 and 11.7 nM, respectively). In addition, several derivatives were selectively active toward primary breast cancer cells compared to normal breast epithelial cells. The most promising derivatives were subsequently tested against the NCI panel of 60 human cancer cell lines and seven derivatives were more potent than COL against leukemia, non–small‐cell lung, colon, CNS and prostate cancers. Finally, COL and two of the most active derivatives were shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants. The present findings indicate that the select COL derivatives constitute promising lead compounds targeting specific types of cancer.

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Animal models of chemotherapy-induced cognitive decline in preclinical drug development

et al. 2021

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Rationale Chemotherapy-induced cognitive impairment (CICI), chemobrain, and chemofog are the common terms for mental dysfunction in a cancer patient/survivor under the influence of chemotherapeutics. CICI is manifested as short/long term memory problems and delayed mental processing, which interferes with a person’s day-to-day activities. Understanding CICI mechanisms help in developing therapeutic interventions that may alleviate the disease condition. Animal models facilitate critical evaluation to elucidate the underlying mechanisms and form an integral part of verifying different treatment hypotheses and strategies. Objectives A methodical evaluation of scientific literature is required to understand cognitive changes associated with the use of chemotherapeutic agents in different preclinical studies. This review mainly emphasizes animal models developed with various chemotherapeutic agents individually and in combination, with their proposed mechanisms contributing to the cognitive dysfunction. This review also points toward the analysis of chemobrain in healthy animals to understand the mechanism of interventions in absence of tumor and in tumor-bearing animals to mimic human cancer conditions to screen potential drug candidates against chemobrain. Results Substantial memory deficit as a result of commonly used chemotherapeutic agents was evidenced in healthy and tumor-bearing animals. Spatial and episodic cognitive impairments, alterations in neurotrophins, oxidative and inflammatory markers, and changes in long-term potentiation were commonly observed changes in different animal models irrespective of the chemotherapeutic agent. Conclusion Dyscognition exists as one of the serious side effects of cancer chemotherapy. Due to differing mechanisms of chemotherapeutic agents with differing tendencies to alter behavioral and biochemical parameters, chemotherapy may present a significant risk in resulting memory impairments in healthy as well as tumor-bearing animals.

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Colchicine in refractory chronic lymphocytic leukemia

Cited by 5 publications

References 10 publications

Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives

Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives

Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells—in vitro and ex vivo study

Animal models of chemotherapy-induced cognitive decline in preclinical drug development

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