PMID- 9865733
OWN - NLM
STAT- MEDLINE
DCOM- 19990125
LR  - 20071115
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 58
IP  - 24
DP  - 1998 Dec 15
TI  - Modeling of the time-dependency of in vitro drug cytotoxicity and resistance.
PG  - 5749-61
AB  - For potential clinical extrapolation of in vitro findings, it is of interest to 
      relate the measured effect of an anticancer agent to concentration and exposure 
      time. The Hill model (A. V. Hill, J. Physiol., 40: iv-vii, 1910) is commonly used 
      to describe pharmacodynamic (PD) effects, including drug-induced growth 
      inhibition of cancer cells in vitro. The IC(X)n x T = k relationship, in which 
      IC(X) is the concentration of agent required to reduce cell growth by X%, T is 
      the exposure time, and n and k are estimable parameters, was first applied to 
      bacterial disinfectant action and then was successfully used to model anticancer 
      drug potency as a function of exposure time (D. J. Adams, Cancer Res., 49: 
      6615-6620, 1989). Our goal was to create a new global PD modeling paradigm to 
      facilitate the quantitative assessment of the growth-inhibitory effect of 
      anticancer agents as a function of concentration and exposure time. Wild-type 
      human ovarian A2780 and ileocecal HCT-8 carcinoma cells and sublines that were 
      resistant to cisplatin (A2780/CP3), doxorubicin (A2780/DX5B), and raltitrexed 
      (RTX) (HCT-8/DW2) were exposed to various anticancer agents, cisplatin, 
      doxorubicin, paclitaxel, trimetrexate, RTX, methotrexate, and AG2034, for periods 
      ranging from 1 to 96 h. Cell growth inhibition was measured with the 
      sulforhodamine B protein dye assay. Patterns of time-dependency of drug potency, 
      slope of the concentration-effect curves, and relative degree of resistance were 
      characterized. Empirical mathematical expressions were built into a global 
      concentration-time-effect model. The global PD model was then fit to the 
      concentration-time-effect data with iteratively reweighted nonlinear regression. 
      Under specific treatment conditions, the examination of the slope and the shape 
      of the concentration-effect curves revealed a large heterogeneity in drug 
      response, e.g., shallow concentration-effect curve or double or triple Hill 
      "roller coaster" concentration-effect curve. These patterns, which were observed 
      at intermediate exposure times in parental and resistant cells for paclitaxel and 
      trimetrexate or only in resistant HCT-8/DW2 cells for RTX, methotrexate, and 
      AG2034, revealed mechanistic insights for the former cases but possible 
      methodological artifacts for the latter cases. The comprehensive PD modeling of 
      the cytotoxic effect of anticancer agents showed that it was possible to modulate 
      drug effect, response heterogeneity, and drug resistance by altering the time of 
      exposure to the agents. This approach will be useful for: (a) describing complex 
      concentration-time-effect surfaces; (b) refining biological interpretations of 
      data; (c) providing insights on mechanisms of drug action and resistance; and (d) 
      generating leads for clinical use of anticancer drugs.
FAU - Levasseur, L M
AU  - Levasseur LM
AD  - Department of Biomathematics, Roswell Park Cancer Institute, Buffalo, New York 
      14263, USA.
FAU - Slocum, H K
AU  - Slocum HK
FAU - Rustum, Y M
AU  - Rustum YM
FAU - Greco, W R
AU  - Greco WR
LA  - eng
GR  - CA16056/CA/NCI NIH HHS/United States
GR  - CA65761/CA/NCI NIH HHS/United States
GR  - RR10742/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents)
SB  - IM
MH  - Antineoplastic Agents/administration & dosage/*pharmacology
MH  - Cell Division/drug effects
MH  - Dose-Response Relationship, Drug
MH  - *Drug Resistance, Neoplasm
MH  - *Models, Biological
MH  - Statistics as Topic
MH  - Time Factors
EDAT- 1998/12/29 00:00
MHDA- 1998/12/29 00:01
CRDT- 1998/12/29 00:00
PHST- 1998/12/29 00:00 [pubmed]
PHST- 1998/12/29 00:01 [medline]
PHST- 1998/12/29 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1998 Dec 15;58(24):5749-61.