PMID- 2819042
OWN - NLM
STAT- MEDLINE
DCOM- 19900105
LR  - 20190613
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 28
IP  - 17
DP  - 1989 Aug 22
TI  - Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies 
      on the mechanism of their inhibition of the binding of colchicine to tubulin.
PG  - 6984-91
AB  - Combretastatin A-4 (CS-A4), 3,4,5-trimethoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, 
      and combretastatin A-2 (CS-A2), 
      3,4-(methylenedioxy)-5-methoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, are 
      structurally simple natural products isolated from the South African tree 
      Combretum caffrum. They inhibit mitosis and microtubule assembly and are 
      competitive inhibitors of the binding of colchicine to tubulin [Lin et al. (1988) 
      Mol. Pharmacol. 34, 200-208]. In contrast to colchicine, drug effects on tubulin 
      were not enhanced by preincubating CS-A4 or CS-A2 with the protein. The mechanism 
      of their binding to tubulin was examined indirectly by evaluating their effects 
      on the binding of radiolabeled colchicine to the protein. These studies 
      demonstrated rapid binding of both compounds to tubulin even at 0 degrees C 
      (binding was complete at the earliest times examined), in contrast to the 
      relatively slow and temperature-dependent binding of colchicine. Although the 
      binding of the C. caffrum compounds to tubulin was quite tight, permitting ready 
      isolation of near-stoichiometric amounts of drug-tubulin complex even in the 
      absence of free drug, both CS-A4 and CS-A2 dissociated rapidly from tubulin in 
      the presence of high concentrations of radiolabeled colchicine. Apparent rate 
      constants for drug dissociation from tubulin at 37 degrees C were 3.2 x 10(-3) 
      s-1 for CS-A4, 4.8 x 10(-3) s-1 for CS-A2, and 2.9 x 10(-5) s-1 for colchicine 
      (half-lives of 3.6, 2.4, and 405 min, respectively). Thus, the effectiveness of 
      the C. caffrum compounds as antimitotic agents appears to derive primarily from 
      the rapidity of their binding to tubulin.(ABSTRACT TRUNCATED AT 250 WORDS)
FAU - Lin, C M
AU  - Lin CM
AD  - Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 
      20892.
FAU - Ho, H H
AU  - Ho HH
FAU - Pettit, G R
AU  - Pettit GR
FAU - Hamel, E
AU  - Hamel E
LA  - eng
GR  - CA-30311-0103/CA/NCI NIH HHS/United States
GR  - CA-30311-01A3/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Bibenzyls)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Plant Extracts)
RN  - 0 (Stilbenes)
RN  - 0 (Tubulin)
RN  - 111394-44-6 (combretastatin A-2)
RN  - 60423-21-4 (2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone)
RN  - 7L6DL16P1T (Tropolone)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - I5590ES2QZ (fosbretabulin)
RN  - L36H50F353 (Podophyllotoxin)
RN  - SML2Y3J35T (Colchicine)
SB  - IM
MH  - Animals
MH  - Bibenzyls/*pharmacology
MH  - Binding Sites
MH  - Brain/metabolism
MH  - Cattle
MH  - Colchicine/*metabolism/pharmacology
MH  - Guanosine Triphosphate/metabolism
MH  - Kinetics
MH  - Macromolecular Substances
MH  - Mitosis/drug effects
MH  - Models, Structural
MH  - Plant Extracts
MH  - Podophyllotoxin/pharmacology
MH  - Protein Binding
MH  - Stilbenes/*pharmacology
MH  - Tropolone/pharmacology
MH  - Tubulin/*metabolism
EDAT- 1989/08/22 00:00
MHDA- 1989/08/22 00:01
CRDT- 1989/08/22 00:00
PHST- 1989/08/22 00:00 [pubmed]
PHST- 1989/08/22 00:01 [medline]
PHST- 1989/08/22 00:00 [entrez]
AID - 10.1021/bi00443a031 [doi]
PST - ppublish
SO  - Biochemistry. 1989 Aug 22;28(17):6984-91. doi: 10.1021/bi00443a031.