PMID- 2961908
OWN - NLM
STAT- MEDLINE
DCOM- 19880217
LR  - 20131121
IS  - 0027-8874 (Print)
IS  - 0027-8874 (Linking)
VI  - 79
IP  - 6
DP  - 1987 Dec
TI  - Facilitated internalization of neocarzinostatin and its lipophilic polymer 
      conjugate, SMANCS, into cytosol in acidic pH.
PG  - 1205-11
AB  - The effects of environmental pH on the binding and cytotoxicity of the antitumor 
      proteins neocarzinostatin (NCS) and SMANCS [copoly(styrene-maleic 
      acid)-conjugated NCS] to cultured cells were studied by using their 
      fluorescent-labeled derivatives (F-drugs). At 37 degrees C the binding of these 
      drugs to HeLa cells was pH dependent: The amount of cell-bound drugs increased 
      with an increase in the acidity of the medium. The pH-dependent change in the 
      binding of the drugs was not as evident at 0 degree C. The cytotoxic action of 
      these drugs was much more rapid at acidic pH compared with that at neutral or 
      slightly alkaline pH. Furthermore, F-drugs could be utilized to probe the 
      microenvironmental pH in Meth-A cells, in which the drug was located by the ratio 
      of fluorescent intensities at 450 and 490 nm. The environment of the cell-bound 
      F-drugs became acidic with incubation time at 37 degrees C but not at 0 degree C. 
      Inasmuch as these drugs directly attack DNA, these results suggest that NCS and 
      SMANCS are translocated across the membrane of acidic vesicles into the cytosol 
      after endocytotic uptake. This hypothesis is also supported by the finding that 
      NH4Cl and chloroquine protected HeLa cells against the cytotoxicity of the drugs. 
      Data also showed that the hydrophobic polyanion conjugate SMANCS had a much 
      greater cell binding (10 times) and more rapid internalization compared with NCS. 
      Taken together, our results show that acidic pH of tumor tissue is preferable for 
      effective binding and internalization into cytosol for NCS and SMANCS.
FAU - Oda, T
AU  - Oda T
AD  - Department of Microbiology, Kumamoto University Medical School, Japan.
FAU - Sato, F
AU  - Sato F
FAU - Maeda, H
AU  - Maeda H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Fluoresceins)
RN  - 0 (Fluorescent Dyes)
RN  - 0 (Furans)
RN  - 0 (Maleic Anhydrides)
RN  - 0 (Polystyrenes)
RN  - 0 (Thiocyanates)
RN  - 0 (poly(maleic acid-styrene)neocarzinostatin)
RN  - 01Q9PC255D (Ammonium Chloride)
RN  - 886U3H6UFF (Chloroquine)
RN  - 9014-02-2 (Zinostatin)
RN  - I223NX31W9 (Fluorescein-5-isothiocyanate)
SB  - IM
MH  - Ammonium Chloride/pharmacology
MH  - Animals
MH  - Antibiotics, Antineoplastic/*metabolism
MH  - Cells, Cultured
MH  - Chloroquine/pharmacology
MH  - Cytosol/metabolism
MH  - Fluorescein-5-isothiocyanate
MH  - Fluoresceins
MH  - Fluorescent Dyes
MH  - Furans/*metabolism
MH  - HeLa Cells/drug effects
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Kinetics
MH  - Maleic Anhydrides/*metabolism/toxicity
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Polystyrenes/*metabolism/toxicity
MH  - Protein Binding
MH  - Thiocyanates
MH  - Zinostatin/analogs & derivatives/*metabolism/toxicity
EDAT- 1987/12/01 00:00
MHDA- 1987/12/01 00:01
CRDT- 1987/12/01 00:00
PHST- 1987/12/01 00:00 [pubmed]
PHST- 1987/12/01 00:01 [medline]
PHST- 1987/12/01 00:00 [entrez]
PST - ppublish
SO  - J Natl Cancer Inst. 1987 Dec;79(6):1205-11.