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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
College of Pharmacy and James Cancer Hospital & Solove Research Institute, The Ohio State University, Columbus, Ohio
Received September 13, 2002; accepted November 1, 2002.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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).
Paclitaxel enhances tubulin polymerization, promotes microtubule assembly,
binds to microtubules, stabilizes microtubule dynamics, induces mitotic block
at the metaphase/anaphase transition, and induces apoptosis
(Parness and Horwitz, 1981;
Manfredi et al., 1982; Jordan
et al., 1993,
1996;
Derry et al., 1995).
Paclitaxel resistance in several resistant sublines is correlated with
reduced intracellular drug accumulation compared with the sensitive parent
cell line (Lopes et al., 1993;
Bhalla et al., 1994;
Jekunen et al., 1994;
Riou et al., 1994;
Speicher et al., 1994).
Changes in the levels of mdr1 P-glycoprotein (Pgp) and tubulin, as
well as tubulin mutations, affect the intracellular paclitaxel accumulation
and are considered the major mechanisms of paclitaxel resistance
(Minotti et al., 1991;
Jachez et al., 1993;
Bhalla et al., 1994;
Haber et al., 1995;
Dumontet et al., 1996;
Giannakakou et al., 1997;
Parekh et al., 1997;
Ranganathan et al., 1998;
Dumontet and Sikic, 1999).
These earlier studies used cell lines in which changes in Pgp or tubulin were
induced either by drug treatment or by gene transfection and, accordingly,
studied each of these parameters as separate entities. However, multiple
groups of investigators have shown that Pgp and tubulins/microtubules are
often altered simultaneously in paclitaxel-resistant cells
(Bhalla et al., 1994;
Haber et al., 1995;
Dumontet et al., 1996). The
effect of simultaneous changes in Pgp and tubulin on the relative importance
of the other parameters on intracellular accumulation is not known and is the
subject of the present study.
As discussed in our previous publications
(Kuh et al., 2000;
Jang et al., 2001), the
accumulation of paclitaxel in cells is determined by several processes, i.e.,
saturable and nonsaturable drug binding to intracellular and extracellular
proteins, cell density, concentrations of tubulins/microtubules, which are the
major intracellular drug binding sites, and drug transport by passive
diffusion and by the energy-dependent Pgp-mediated efflux. These processes, in
turn, are dependent on the extracellular and intracellular drug
concentrations, and are interrelated. For example, the contribution of
Pgp-mediated paclitaxel efflux to the overall efflux decreases with increasing
extracellular drug concentrations (Jang et
al., 2001). Paclitaxel binding to tubulins/microtubules is
saturable, and the bound fraction diminishes with increasing extracellular
drug concentrations (Manfredi et al.,
1982; Jordan et al.,
1993; Kuh et al.,
2000). In addition, changes in the amount of tubulins/microtubules
result in parallel changes in the intracellular paclitaxel binding capacity,
and changes in the composition of 
-tubulin isotypes alter the paclitaxel
binding affinity, whereas mutation of -tubulin reduces the binding
affinity (Haber et al., 1995;
Dumontet et al., 1996;
Derry et al., 1997;
Giannakakou et al., 1997;
Ranganathan et al., 1998).
These tubulin-related changes alter the fraction of free drug available for
efflux and therefore may alter the importance of Pgp efflux. An examination of
the effects of these various determinants of intracellular paclitaxel
accumulation has not been possible because of the inherent difficulty of
engineering stable cell lines with systematic changes in the levels of Pgp
and/or tubulins/ microtubules, and/or the drug binding affinity to tubulins/
microtubules.
The present study used a computational approach to depict the effects of
Pgp efflux and drug binding to tubulins/microtubules, singly and in
combination, on intracellular paclitaxel accumulation. The studies were
performed using our previously described intracellular pharmacokinetic model
and model parameters obtained for human breast MCF7 cells and the
corresponding mdr1-transfected subline (BC19), which showed a
>9-fold higher Pgp level (Fairchild et
al., 1990; Li and Au,
2001). The parameters representing Pgp-mediated drug efflux and
intracellular binding (i.e., number of Pgp molecules, number of paclitaxel
binding sites, and paclitaxel binding affinity) were altered, singly or in
combination, and were used to generate computer simulations. The results
demonstrate that the effects of these parameters on intracellular paclitaxel
accumulation depended on extracellular drug concentrations and were
interdependent. These data further provide quantitative measurements of the
relationship between tubulins/microtubules, kinetics of Pgp efflux,
extracellular (e.g., plasma) drug concentration, and intracellular drug
accumulation and retention.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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; Jang et al.,
2001). Briefly, the model included 1) saturable binding of
paclitaxel to proteins in the extracellular compartment
(Song et al., 1996), 2)
saturable and nonsaturable binding of paclitaxel to cellular components
(Manfredi et al., 1982), 3)
timeand concentration-dependent changes in microtubule mass
(Jordan et al., 1993,
Derry et al., 1995), 4) timeand
concentration-dependent changes in cell number
(Kuh et al., 2000), and 5)
saturable Pgp-mediated drug efflux (Jang
et al., 2001). We assumed that 1) drug uptake into cells is by
passive diffusion, 2) drug efflux from cells is by passive diffusion and
Pgp-mediated efflux, and 3) only unbound drug molecules participate in the
uptake and efflux processes.
Equations 1 and 2 describe the time-dependent changes in intracellular and
extracellular drug concentrations, respectively. Derivations of these
equations have been described elsewhere
(Kuh et al., 2000;
Jang et al., 2001).
 | (1) |
 | (2) |
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 |
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Ctotal,c and Ctotal,m are total (i.e., free plus bound) drug concentrations in cells and medium, respectively. A separate study found that >95% of the cell-associated paclitaxel was accounted for the drug located in cellular components and organelles (J. Kim and J. L.-S. Au, unpublished observations). Hence, intracellular drug concentration equals Ctotal,c. Cfree,c and Cfree,m represent free drug concentrations in cells and medium, respectively. Vc is the total cell volume. Vm is the volume of medium. CLf,d is the clearance of free drug per cell by passive diffusion. Jmax is maximum efflux rate by Pgp per cell. KM,Pgp is the dissociation constant of Pgp-mediated efflux. Bmax,c and Bmax,m are the numbers of saturable drug binding sites in cells and medium, respectively. Kd,c and Kd,m are dissociation constants for drug binding to saturable binding sites in cells and medium, respectively. NSB is the proportionality constant for nonsaturable drug binding in cells. Vone cell is the average volume of a single cell. ICN is the initial cell number at time 0. kcell number is the rate constant for changes in cell number. Bmax,c,initial is Bmax,c at time 0. kBmax,c is the rate constant for changes in Bmax,c.
Simulation Studies. Equations 1 and 2 were used to simulate the paclitaxel concentration-time profiles in cells as a function of initial extracellular drug concentration, intracellular drug binding capacity and affinity, and maximum Pgp efflux rate. These simulations provided a quantitative measure of the effects of maximum Pgp efflux and drug binding, individually and collectively, on intracellular paclitaxel pharmacokinetics. For the remainder of this report, changes in the maximum Pgp efflux rate are assumed to reflect changes in Pgp expression.
All simulations used an initial cell number of 1 million and a medium
volume of 1 ml. Initial simulations were performed using the parameter values
experimentally obtained in MCF7 and BC19 cells. At each condition,
intracellular drug concentration-time profiles were simulated, and the
intracellular drug concentrations at 4 h, which is the time interval when
intracellular and extracellular drug concentrations reached an apparent steady
state under most conditions, were compared
(Jordan et al., 1996;
Kuh et al., 2000;
Jang et al., 2001). WIN-NONLIN
(SCI Software, Lexington, KY) was used for simulations. The parameter values
were further altered according to literature reports, as described below and
summarized in Table 1.
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Evaluation of the effect of extracellular concentrations was conducted
using four initial extracellular concentrations, i.e., 1, 2, 10, and 1000 nM,
which are within the clinically relevant range and the range in which the role
of Pgp-mediated efflux varies from major to minor relative to diffusion
(Jang et al., 2001).
Changes in the amount of tubulins/microtubules were represented by altering
the number of saturable intracellular binding site
(Bmax,c). The value of Bmax,c in MCF7
and BC19 cells was 60 µM (Kuh et al.,
2000; Jang et al.,
2001). Resistant cells selected by continuous paclitaxel treatment
showed a 2-fold increase in the tubulin amount
(Haber et al., 1995;
Dumontet et al., 1996). Hence,
simulations used three Bmax,c values: low binding capacity
(30 µM), moderate binding capacity (60 µM), and high binding capacity
(120 µM).
Changes in the drug binding affinity of tubulins/microtubules were
represented by changes in the value of the dissociation constant of saturable
intracellular drug binding (Kd,c). The
Kd,c value in MCF7 and BC19 cells was 5 nM. To the best of
our knowledge, there are no data on the binding affinity of paclitaxel to
tubulins/microtubules in parent and resistant cancer cells. A study using
different -tubulin isotypes purified from bovine brain tubulin showed a
2- to 6-fold difference in the number of bound paclitaxel molecules required
for tubulin polymerization (Derry et al.,
1997). Hence, simulations used two Kd,c
values: low binding affinity (20 nM) and high binding affinity (5 nM).
Changes in Pgp expression were represented by altering the maximum
Pgp-mediated efflux rate (Jmax) from 0 to 280 x
10–6 pmol/h. These Jmax values
were observed in MCF7 cells with negligible Pgp expression and in
mdr1 gene-transfected BC19 cells
(Jang et al., 2001).
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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), the time
course of intracellular paclitaxel accumulation varies with extracellular drug
concentration. At low extracellular concentration (<10 nM), the
intracellular concentrations initially increased, reaching an apparent steady
state at about 4 h, and, due to the formation of new cells (due to incomplete
inhibition of cell proliferation) and redistribution of paclitaxel over the
increased cellular mass, gradually declined after 12 h. At high extracellular
concentrations of 1000 nM, the intracellular concentration rose rapidly to
reach an apparent steady state at 4 h, and, due to the drug-induced
enhancement of tubulin/microtubule levels and, consequently, the increase in
intracellular drug binding, continued to increase slowly by 
35% from 4 to
24 h. A comparison of the intracellular concentrations, achieved at 4 h or
before changes in cell number or tubulin/microtubule content occurred, showed
that clinically relevant changes in each of the four above-mentioned
parameters resulted in 1.04- to 1243-fold changes in intracellular drug
concentration (Table 1).
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As shown in Table 1, the changes in intracellular concentration due to increases in extracellular concentration are different in cells that express different Pgp levels, different binding capacity, or different binding affinity. Hence, the data in Table 1 were further analyzed to depict the changes of intracellular concentration for various combinations of the four parameters. The results are summarized in Tables 2, 3, 4, 5. For example, Table 2 shows the effect of changing the extracellular concentration in the presence of different Pgp expression (low or high), different binding affinity (low or high), or different binding capacity (low, moderate, or high). Similarly, Tables 3, 4, 5 show the effects of intracellular binding capacity, binding affinity, and Pgp expression in the presence of different values of the other parameters, respectively.
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In the following discussions, the numerical values of the four parameters are as follows: initial extracellular concentrations, 1 (low), 2 (low), 10 (moderate), and 1000 nM (high); binding capacity or Bmax,c, 30 (low) 60 (moderate), and 120 µM (high); binding affinity or Kd,c, 20 (low) and 5 nM (high); and Pgp expression or Jmax values, 0 (low) and 280 x 10–6 pmol/h (high).
Effect of Extracellular Drug Concentrations on Paclitaxel Accumulation in Cells. As expected, higher extracellular paclitaxel concentrations resulted in higher intracellular concentrations; 2-, 10-, and 1000-fold increases in extracellular drug concentration yielded, on average, 2-, 9.9-, and 573-fold increases in intracellular accumulation, respectively (Table 2).
Two differences were observed at low (1–10 nM) and high (1000 nM) extracellular drug concentrations. First, when extracellular paclitaxel concentration increased from 1 to 2 or 10 nM, intracellular concentration increased linearly with extracellular concentration. However, at a much higher extracellular concentration of 1000 nM, intracellular concentration increased linearly with extracellular concentration only under the condition of low binding affinity and high Pgp expression (irrespective of binding capacity), whereas all other conditions resulted in less than a 1:1 linear increase (Tables 1 and 2). Second, at low extracellular concentration range (1–10 nM), the effect of extracellular concentrations on intracellular accumulation was constant regardless of the values of the other three parameters. In comparison, when extracellular paclitaxel concentration increased from 1 to 1000 nM, the effect of extracellular concentrations on intracellular accumulation was dependent on the values of the other three parameters, was greater at low intracellular drug binding affinity compared with high binding affinity (2-fold difference), and was greater at high Pgp expression compared with lower Pgp expression (2.5-fold difference), but was only slightly altered by a 4-fold change in binding capacity (<20% difference) (Table 2).
Effect of Intracellular Drug Binding Capacity on Paclitaxel Accumulation
in Cells. In general, increases in binding capacity resulted in increased
intracellular drug accumulation, whereas decreases in binding capacity
resulted in decreased intracellular accumulation; a 2-fold increase in binding
capacity yielded 50% increase in intracellular accumulation and a 2-fold
decrease produced an 30% decrease
(Table 3). The effect of
binding capacity on intracellular drug accumulation was dependent on the
values of the other three parameters, was greater at high extracellular drug
concentration compared with low extracellular concentration (1.8-fold
difference), and was greater at high Pgp expression compared with low Pgp
expression (1.5-fold difference), but was only slightly affected by a 4-fold
change in binding affinity (<20% difference).
Effect of Intracellular Paclitaxel Binding Affinity on Drug Accumulation
in Cells. In general, decreasing paclitaxel binding affinity resulted in
decreased intracellular drug accumulation; a 4-fold decrease in binding
affinity yielded 30% decrease in intracellular concentration
(Table 4). The effect of
binding affinity on intracellular drug accumulation was dependent on the
values of the other three parameters, was greater at low extracellular drug
concentration compared with high extracellular concentration (6-fold
difference), and was greater in high Pgp expression compared with lower Pgp
expression (2-fold difference), but was only slightly altered by a 4-fold
change in the binding capacity (35% difference).
Effect of Pgp Expression on Paclitaxel Accumulation in Cells. In
general, higher Pgp expression resulted in reduced intracellular paclitaxel
accumulation; an increase of the maximum Pgp-mediated efflux rate from 0 to
280 x 10–6 pmol/h resulted in 40%
decrease in intracellular concentration
(Table 5). The effect of Pgp
expression on intracellular drug accumulation was dependent on the values of
the other three parameters and was greater at low extracellular concentration
compared with high extracellular concentration (4-fold difference), but was
only slightly altered by a 4-fold change in the binding capacity (20%
difference) or a 4-fold change in the binding affinity (40% difference). The
drastically reduced effect of Pgp expression on intracellular drug
accumulation at high extracellular drug concentration is in agreement with the
saturation of the Pgp-mediated efflux at high drug concentration as shown
previously (Jang et al.,
2001).
Interdependence of Pgp-Mediated Efflux, Intracellular Drug Binding Capacity, and Affinity in Paclitaxel Accumulation in cells. To demonstrate the interdependence of the effects of drug binding to tubulins/microtubules and Pgp efflux, we performed additional simulations by systematically altering the values of maximum Pgp efflux rate, number of intracellular drug binding sites and dissociation constant of intracellular drug binding, at an extracellular drug concentration of 1 nM. The results, shown in Fig. 2, indicate nearly identical intracellular paclitaxel concentrations in several different situations. For example, irrespective of the rate of Pgp-mediated efflux, identical intracellular drug concentrations were observed for two situations with different binding capacities and binding affinities (i.e., combination of binding capacity of 120 µM and binding affinity of 20 nM versus combination of binding capacity of 30 µM and binding affinity of 5 nM). Furthermore, an increase of binding affinity by 4-fold, i.e., a decrease in dissociation constant of intracellular drug binding from 20 to 5 nM, and an increase of the Pgp efflux from 0 to 140 x 10–6 pmol/h resulted in identical changes in intracellular drug concentrations. Likewise, an increase of binding capacity by 2-fold from 60 to 120 µM and an increase of the Pgp efflux from 70 to 210 x 10–6 pmol/h resulted in similar changes. These results showed that changes in one or more parameters were offset by changes in other parameters.
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The simulation results also showed that under certain situations, a higher Pgp expression might result in the counterintuitive results of a higher paclitaxel accumulation. For example, results in Fig. 2 show that paclitaxel concentration in cells with high Pgp expression (Jmax of 280 x 10–6 pmol/ h), high binding capacity (Bmax,c of 120 µM), and high binding affinity (Kd,c of 5 nM) was higher than in cells with low Pgp (Jmax of 0 pmol/h), low binding capacity (Bmax,c of 30 µM), and low binding affinity (Kd,c of 20 nM).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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40% decrease in intracellular accumulation. These results, in turn,
suggest that although Pgp efflux, paclitaxel binding capacity, and affinity
play a role in intracellular drug accumulation, their effects are far less
important compared with extracellular drug concentration. Our results indicate
that within the clinically relevant drug concentration range of 1 to 1,000 nM,
the presentation or delivery of paclitaxel to tumor cells, rather than tumor
biological factors including Pgp expression, and amount and binding affinity
of tubulins/microtubules, is the major determinant of intracellular drug
accumulation. Our results further indicate that the relative contributions of the four parameters to the intracellular paclitaxel accumulation were interdependent, as follows. The relationship between extracellular and intracellular drug concentrations was highly dependent on intracellular drug binding affinity and Pgp expression but was only slightly affected by intracellular binding capacity. The relationship between intracellular drug binding capacity and intracellular drug accumulation was highly dependent on the extracellular drug concentration and Pgp expression but was only slightly affected by intracellular binding affinity. The relationship between intracellular binding affinity and intracellular drug accumulation was highly dependent on extracellular drug concentration and Pgp expression but was only slightly affected by intracellular binding capacity. Finally, the relationship between Pgp expression and intracellular drug accumulation was highly dependent on extracellular drug concentration but was only slightly affected by intracellular drug binding capacity or intracellular binding affinity.
We have also shown that omission of one or more of these factors in the
experimental design would lead to erroneous conclusions on the importance of
other factors. For example, an experiment conducted using 1000 nM
extracellular drug concentration would suggest binding affinity of
tubulins/microtubules as an unimportant determinant of drug accumulation since
a 4-fold change in this parameter resulted in only minor changes in drug
accumulation, whereas a similar experiment conducted at 1 nM concentration
would indicate the opposite. Likewise, simultaneous changes in the Pgp efflux
rate, drug binding sites, and binding affinity may alter the relative
importance and offset the effects of each other; e.g., the effect of a 3-fold
increase in the Pgp efflux rate was offset by a 2-fold increase in
intracellular saturable drug binding site. Hence, depending on the status of
the intracellular drug binding, changes in intracellular drug accumulation may
occur with or without changes in Pgp expression. Conversely, our results
indicate that the importance of Pgp is dependent on the amount and drug
binding affinity of tubulins/microtubules in cells as well as the
extracellular drug concentration, and that changes in Pgp expression may or
may not translate to altered drug accumulation. This may, in part, explain the
controversy regarding the importance of Pgp in tumor sensitivity/resistance to
paclitaxel; some studies indicate Pgp as an important prognostic indicator of
tumor response, whereas other studies indicate the opposite conclusion
(Arbuck et al., 1994;
Fisher and Sikic, 1995). This
issue deserves consideration since it is well known that paclitaxelresistant
cells show simultaneous changes in Pgp expression, total tubulin amount, and
composition of tubulin isotypes (Haber et
al., 1995; Dumontet et al.,
1996).
In conclusion, we have demonstrated the complex interdependent effects of extracellular drug concentration, Pgp expression, intracellular drug binding capacity, and binding affinity on intracellular paclitaxel accumulation. Our results further demonstrate that omission of one or more of these factors may result in erroneous conclusions. We propose that studies on the effects of Pgp expression and changes in tubulins/microtubules on intracellular paclitaxel accumulation should include multiple extracellular drug concentrations within the clinically relevant range, and include evaluation of simultaneous changes of these factors. Furthermore, our simulation results suggest that within the clinically relevant drug concentration range, extracellular drug concentration is the most important determinant of intracellular drug accumulation. These results justify further studies to verify that changes in dosing or treatment schedule to provide greater drug delivery to tumor cells may be more effective than modifying tumor biological factors for increasing drug accumulation in tumor cells, and to establish pharmacokinetic-pharmacodynamic models to examine the schedule-dependent antitumor activity of paclitaxel. Finally, the present study represents an attempt to use computational modeling to address the complex interplay between Pgp and drug binding to intracellular macromolecules. Such an approach can be expanded to evaluate other agents that are Pgp substrates and are highly bound to intracellular macromolecules.
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Footnotes |
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ABBREVIATIONS: mdr1, multidrug resistance gene 1; Pgp, P-glycoprotein; Jmax, maximum efflux rate by Pgp per cell; Bmax,c, the number of saturable drug binding sites in cells; Kd,c, dissociation constants for drug binding to saturable binding sites in cells.
1 Current Address: Office of Clinical Pharmacology and Biopharmaceutics,
Center for Drug Evaluation and Research, Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857. 
Address correspondence to: Jessie L.-S. Au, College of Pharmacy, 500 West 12th Avenue, Columbus, OH 43210. E-mail: au.1{at}osu.edu
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