Evidence map›Paper›PMID 20937594›Full record

ArticleMolecular cancer therapeutics2010

Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules.

Manu Lopus, Emin Oroudjev, Leslie Wilson, Sharon Wilhelm, Wayne Widdison, Ravi Chari, Mary Ann Jordan

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular cancer therapeutics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers.

0numbers the graph read from it
0cells of the map it votes in
96citing papers in PubMed
4.7field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

96 citing papers in PubMed, 223 citations in OpenAlex.

  1. Trial
  2. Trial
  3. Trial
  4. Trial
  5. Observational
  6. Review
  7. Article
  8. Review
  9. Article
  10. Review
  11. Review
  12. Article
  13. Article
  14. Review
  15. Review
  16. Review
  17. Review
  18. Article
  19. Review
  20. Article

36 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 2 institutions in 1 country.

Manu LopusDepartment of Molecular, Cellular, and Developmental Biology, and Neuroscience Research Institute, University of California, Santa Barbara, California 93106-9610, USA.
Emin Oroudjev
Leslie Wilson
Sharon Wilhelm
Wayne Widdison
Ravi Chari
Mary Ann Jordan
University of California, Santa Barbara · USImmunoGen (United States) · US

Funding

Mechanism &Control of Brain Microtubule DynamicsR01NS013560 · NINDS · UNIVERSITY OF CALIFORNIA SANTA BARBARA · PI WILSON, LESLIE · 1985 to 2009
$2.9M
Mechanisms of Action of Anti-Mitotic DrugsR01CA057291 · NCI · UNIVERSITY OF CALIFORNIA SANTA BARBARA · PI JORDAN, MARY ANN · 1992 to 2007
$2.2M
NCI NIH HHS CA 57291NCI NIH HHS R01 CA057291NINDS NIH HHS NS13560NINDS NIH HHS R01 NS013560
6 · The paper itself

Abstract

Maytansine is a potent microtubule-targeted compound that induces mitotic arrest and kills tumor cells at subnanomolar concentrations. However, its side effects and lack of tumor specificity have prevented successful clinical use. Recently, antibody-conjugated maytansine derivatives have been developed to overcome these drawbacks. Several conjugates show promising early clinical results. We evaluated the effects on microtubule polymerization and dynamic instability of maytansine and two cellular metabolites (S-methyl-DM1 and S-methyl-DM4) of antibody-maytansinoid conjugates that are potent in cells at picomolar levels and that are active in tumor-bearing mice. Although S-methyl-DM1 and S-methyl-DM4 inhibited polymerization more weakly than maytansine, at 100 nmol/L they suppressed dynamic instability more strongly than maytansine (by 84% and 73%, respectively, compared with 45% for maytansine). However, unlike maytansine, S-methyl-DM1 and S-methyl-DM4 induced tubulin aggregates detectable by electron microscopy at concentrations ≥2 μmol/L, with S-methyl-DM4 showing more extensive aggregate formation than S-methyl-DM1. Both maytansine and S-methyl-DM1 bound to tubulin with similar K(D) values (0.86 ± 0.2 and 0.93 ± 0.2 μmol/L, respectively). Tritiated S-methyl-DM1 bound to 37 high-affinity sites per microtubule (K(D), 0.1 ± 0.05 μmol/L). Thus, S-methyl-DM1 binds to high-affinity sites on microtubules 20-fold more strongly than vinblastine. The high-affinity binding is likely at microtubule ends and is responsible for suppression of microtubule dynamic instability. Also, at higher concentrations, S-methyl-DM1 showed low-affinity binding either to a larger number of sites on microtubules or to sedimentable tubulin aggregates. Overall, the maytansine derivatives that result from cellular metabolism of the antibody conjugates are themselves potent microtubule poisons, interacting with microtubules as effectively as or more effectively than the parent molecule.

Indexed as

AnimalsAntineoplastic Agents, PhytogenicBinding SitesCattleImmunoconjugatesMaytansineMiceMicrotubulesPolymersSolubilityTubulinAntineoplastic Agents, PhytogenicImmunoconjugatesMaytansinePolymersTubulin

Identifiers

PMID20937594
PMCPMC2954514
OpenAlexW2097529056

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.