Download Cytotoxicity, Radiosensitization, Antitumor

[CANCER RESEARCH 50, 6971-6975. November 1. 1990]
Cytotoxicity, Radiosensitization, Antitumor Activity, and Interaction with
Hyperthermia of a Co(III) Mustard Complex1
Beverly A. Teicher,2 Michael J. Abrams, Kristina W. Rosbe, and Terence S. Herman
Dana-Farber Cancer Institute [B. A. T., K. W. R., T. S. H.J and Joint Center for Radiation Therapy fB. A. T., T. S. H.], Boston, Massachusetts 02II5, and Johnson-Matthey,
Inc., West Chester, Pennsylvania 19380 [M. J. A.]
ABSTRACT
A complex of Co(III) with a nitro group and a bis(2-chloroethyl)amine
moiety was prepared in an effort to develop a new anticancer agent with
radiosensitizing capabilities, direct antitumor activity, and the ability to
interact positively with clinically relevant hyperthermia temperatures.
The activity of this drug was compared to a similar Co(III) complex,
nitro-bis(2,4-pentanedionato)(pyridine)cobalt(III)
(Co(Py)], which bears
a pyridine moiety mustard of bis(2-chloroethyl)amine and should have
no alkylating abilities. In EMT6 cells nitro-bis(2,4-pentanedionatoXbis(2-chloroethyl)amine)cobalt(III)
(Co(BCA)j was significantly
more cytotoxic than <'o(Py) and both drugs were more toxic toward
normally oxygenated than hypoxic cells. Hyperthermia (42°C,1 h)
increased the slope of the concentration-dependent survival curve for
Co(BCA) but not for Co(Py) in normally oxygenated EMT6 cells.
Co(BCA) was an effective radiosensitizer of hypoxic EMT6 cells in vitro,
producing a dose-modifying factor of 2.40. In the human squamous cell
line SCC-25 and the nitrogen mustard-resistant subline SCC-25/HN2
Co(BCA) was more cytotoxic than Co(Py), and the lethality of Co(BCA)
was only minimally diminished in the SCC-25/HN2 line. In mice bearing
the I 1210 leukemia i.p., Co(BCA) had a broad range of therapeutically
effective dosage and produced a >60-day increase in life span at a dose
20-fold less than was lethally toxic. In addition, in the FSalIC murine
fibrosarcoma, Co(BCA) produced a tumor growth delay of 9.4 days at 75
mg/kg i.p. daily x 5, but Co(Py) produced a delay of only 2.9 days at 50
mg/kg daily x 5 and was lethally toxic above this dose. These results
indicate that Co(BCA) has significant antineoplastic effects in vitro and
in vivo and interacts positively with both radiation and mild hyperthermia.
Its broad therapeutic dose range further suggests potential clinical utility.
INTRODUCTION
Complexes of many transition metals have demonstrated
cytotoxicity in cell culture and/or antitumor activity in tumorbearing animals (1-4). Only complexes of platinum, however,
are currently in routine clinical use (5-10). A wide variety of
metal complexes have also been shown to be radiation-sensitizers of mammalian and/or bacterial cells. These include com
plexes of Ag(I), Cu(I), Cu(II), Zn(II), Hg(II), Rh(II), Ru(II),
Pd(II), Pt(II), Ru(III), Co(III), and Fe(III) (11). We have pre
viously examined the in vitro radiosensitizing potential of 100
¿¿M
concentrations of a series of 12 Co(III) complexes ranging
in structure from hexanitro-Co(III) to hexammine-Co(III) (12).
At this relatively low drug concentration, a wide range of
radiosensitization activity was observed. Although the most
active complexes in this study contained coordinated nitro
ligands, the presence of nitro ligands on the complex was not a
requirement for radiosensitizing capability (12).
Complexes of Co(III) are kinetically inert octahedral coor
dination complexes. This inertness is due to the </6 low spin
electron configuration of trivalent cobalt (13). Kinetically inert
Received 4/16/90; accepted 8/1/90.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1This work was supported by NIH Grant R01-CA36508.
2To whom requests for reprints should be addressed, at Dana-Farber Cancer
Institute, 44 Binney St., Boston, MA 02115.
transition metal complexes [e.g., Rh(III) and Cr(III)] undergo
the water exchange reaction relatively slowly, with half-lives of
about 1 day (14). In contrast, complexes of kinetically labile
metal ions [e.g., Mn(II), Cr(II)] undergo this reaction with halflives of less than l s (14). The biological consequence of kinetic
inertness is that many Co(III) complexes will remain intact
when added to a culture medium or injected into animals and
should arrive at their cellular targets with their ligand configu
ration intact.
In an effort to further increase antitumor activity and the
radiosensitizing potential of Co(III) complexes, we have syn
thesized a complex of Co(III) with an alkylating moiety. In this
report we detail the synthesis, in vitro cytotoxicity, and initial
in vivo antitumor studies with Co(BCA),3 which bears both a
nitro group and a bis(2-chloroethyl)amine moiety. To evaluate
the effect of the bifunctional alkylating group on Co(BCA), an
analogous Co(III) complex bearing a pyridine moiety instead,
Co(Py), was prepared and compared to Co(BCA).
MATERIALS
AND METHODS
Preparation of Co(BCA). To prepare Co(BCA), 1.5 g of
Na[Co(NO2)2(acetylacetonate)2] (4.6 mmol) were dissolved in water (60
ml) and the red-brown solution was filtered to remove residual insoluble
material (15). To this stirred solution were added bis(2-chloroethyl)amine-HCl (0.82 g, 4.6 mmol) in water (10 ml) and sodium
bicarbonate (0.39 g, 4.6 mmol) in water ( 10 ml). The solutions of BCAHC1 and NaHCOj were combined immediately before addition to the
reaction mixture. After 30 min the brown microcrystalline product was
collected, washed with ether, and dried in vacuo. The yield was 0.45 g
(24% based on Co). The calculated atomic weight percentage compo
sition for C,4H23CL2CoNo2O6 is C, 37.78%; H, 5.22%; N, 6.29%; Cl,
15.93%. Actual measurements yielded C, 37.92%; H, 5.10%; N, 6.54%;
Cl, 16.22%. Co(Py) was prepared analogously and characterized as
described previously (15). These materials are readily soluble in polar
organic solvents. Both cobalt complexes are prepared freshly just prior
to use in cell culture or animals.
Mustargen (nitrogen mustard) was obtained from the Dana-Farber
Cancer Institute pharmacy. Nor-nitrogen mustard [bis(chloroethyl)amine] was purchased from Aldrich Chemical Co (Milwaukee, WI).
These agents were prepared freshly just prior to use in cell culture or
animals.
Cell Lines. The EMT6 mammary tumor cell line has been widely
used for the study of antineoplastic agents (16-18). The experiments
described here were performed using asynchronous EMT6 monolayers
in exponential growth, in Waymouth's medium supplemented with
antibiotics (Grand Island Biological Co., Grand Island, NY) and 15%
newborn calf serum (Hyclone Laboratories, Logan, UT). This cell line
has a plating efficiency of 65-80% and a doubling time of 16-19 h in
vitro (\S).
The SCC-25 human squamous cell carcinoma cell line retains an
epithelioid appearance and grows without the aid of a feeder layer (19).
It has a plating efficiency of 15-20%, as judged by plating single
colonies on plastic. The cells were grown on Dulbecco's modified
3The abbreviations used are: Co(BCA), nitro-bis(2,4-pentanedionato)(bis(2chloroethyl)amine)cobalt(III); BCA, bis(2-chloroethyl)amine-HCl; Co(Py), nitrobis(2,4-pentanedionato)(pyridine)cobalt(III);
PBS, phosphate-buffered 0.9% sa
line.
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ANTITUMOR Co(l][) MUSTARD COMPLEX
Eagle's medium supplemented with 5% fetal bovine serum and anti
biotics. For the SCC-25 line, hydrocortisone (0.4 Mg/ml) was included
in the medium (20).
The nitrogen mustard-resistant subline SCC-25/HN2 was developed
through escalating selection pressure methodology (21). Nearly con
fluent 100-mm1 dishes were treated with approximately the concentra
tion of nitrogen mustard that would kill 90% of the cells in 1 h, washed
3 times with PBS, and covered with fresh medium plus serum. The
dose of nitrogen mustard treatment was escalated at a rate of 15-20%/
week, and the cells were treated weekly unless there was no evidence of
cell growth between treatments. After 14 months of treatment, clones
were developed and screened for resistance to nitrogen mustard for
doubling times similar to that of SCC-25 parent cell line (21). Other
characteristics of the SCC-25/HN2 line have been described (22).
Cytotoxicity Studies. EMT6 cells, SCC-25 cells, or SCC-25/HN2
cells in exponential growth were exposed for l h to concentrations
ranging from 5 to 500 //M of the cobalt complexes, nitrogen mustard,
or BCA. The cells were then washed 3 times with PBS and cloned as
described previously (12, 16, 23).
Hyperthermia Studies. Exponentially growing EMT6 cells were ex
posed to the study drugs at 37°Cor 42°Cfor 1 h. Heating was
mean ±SE for the treatment group compared to the control. Tumor
volume was calculated as a hemiellipsoid. Untreated tumors reach 500
mm1 in 14.0 ±0.3 days (27, 28).
In Vivo Data Analysis. Data on the delay of tumor growth were
analyzed with a BASIC program for the Apple II + microcomputer.
The program derived the best-fit curve for each set of data and then
calculated the median, mean, and SE for individual tumor volumes and
the day on which each tumor reached 500 mm\
RESULTS
The structures of Co(BCA) and Co(Py) are shown in Fig. 1.
The bulk of the pyridine ligand is similar to that of the bis-(2chloroethyl)amine ligand; however, the pyridine ligand does not
have the bifunctional alkylating capability of the bis-(2-chloroethyl)amine. In vivo, Co(BCA) may be a prodrug, since in this
complex the bis-alkylating moiety of Co(BCA) should be inac
tivated via complexation of the nitrogen lone pair to the Co(III)
ion. Intracellularly, free BCA should be released upon reduction
of Co(BCA) to a Co(II) species.
accomplished in a Plexiglas water tank with a continuous in flow and
Co(BCA) was more cytotoxic toward EMT6 cells under both
out-flow system controlled by a water temperature controller (Braun
normally oxygenated and hypoxic conditions than was Co(Py)
Thermomix 1460; Braun Instruments) (24). Cells underwent heating
(Fig. 2). Both cobalt complexes were more cytotoxic toward
in sealed plastic flasks (Falcon Plastics) containing 5 ml of complete
medium plus drug. Water temperature could be maintained at ±0.10°C normally oxygenated EMT6 cells than toward hypoxic EMT6
cells. Co(BCA) at 100 MMfor 1 h killed about 1 log of normally
(SD).
oxygenated EMT6 cells. The concentration of Co(BCA) re
Production of Hypoxia. To produce hypoxia, flasks containing EMT6
quired to kill 1 log of hypoxic EMT6 cells after a 1-h exposure
cells in complete medium plus serum were fitted with rubber sleeve
to the drug was about 140 ¿¿M.
A drug concentration of about
serum stoppers and exposed to a continuously flowing 95% nitrogen/
5% CO2 humidified atmosphere for 4 h at 37°C(23). Parallel flasks
340 /UMCo(Py) for 1 h was required to produce 1 log of cell
were maintained in 95% air/5% CO2. At this time, the drug (0.10 ml)
kill of normally oxygenated EMT6 cells, while a concentration
or vehicle (PBS, 0.10 ml) was added to the flasks by injection through
of much greater than 500 UM Co(Py) for 1 h would have been
the rubber stopper, without disturbing the hypoxia.
needed to produce the same level of cell kill of hypoxic EMT6
Radiation Survival Studies. Hypoxia was produced as described
cells. BCA shows no difference in cytotoxicity toward normally
above. For radiation, the hypoxic flasks were placed in an insulated
chamber at 37°Cfilled with 95% nitrogen/5% CO2 atmosphere. The
cells were irradiated with a "7Cs radiation unit (Gammacell 40: Atomic
Energy of Canada, Ltd.) at a dose rate of approximately 1.05 Gy/min.
Drug-treated cells were irradiated so that the irradiation was complete
1 h after addition of the drug. X-ray doses of 5, 10, 15, and 20 Gy were
used. The baseline oxygen enhancement ratio in the EMT6 cell line
was 2.9 (12, 16).
In Vitro Data Analysis. Quantitative analysis of dose-response curves
for cell survival was performed using the log-probit iterative least
squares method. This approach is a statistically rigorous and objective
means for determining the slope of the dose-response curve. Correlation
coefficients for the linear log-probit line and x2 analysis for goodness
of fit were also calculated. The dose-modifying factors were calculated
as the ratio of the slopes of the survival curves obtained with radiation
alone and radiation in the presence of the test drug.
In Vivo Studies. The LI210 leukemia was grown in DBA mice (The
Jackson Laboratory, Bar Harbor, ME). For experiments, IO6 tumor
cells were implanted i.p. on day 0. Drug treatment was begun on day 1
and drugs were administered daily for 5 days. Treatment outcome was
assessed as increase in life span of treated compared to untreated control
animals (25).
The FSall fibrosarcoma (26) was carried in male C3H/He mice (The
Jackson Laboratory). For the experiments, 2 x IO6tumor cells prepared
from a brei of several stock tumors were implanted i.m. into the legs of
male C3H/He mice 8 to 10 weeks of age. When the tumors were
approximately 100 mm3 in volume, treatment was initiated. In those
groups receiving drug, Co(BCA) (10, 25, 50, or 75 mg/kg) or Co(Py)
(25, 50, or 75 mg/kg) in phosphate-buffered 0.9% saline (0.2 ml) was
injected i.p. daily for 5 days. The progress of each tumor was measured
thrice weekly. Tumor growth delay is the number of days for the tumors
in treated animals to reach 500 mm,' compared to the tumor of
untreated controls. Each treatment group had seven animals and the
experiment was repeated 3 times. Days of tumor growth delay are the
CH,CH,CÕ
CH,
HN
IcH.CH.CI
C-CH,
NO,
NO,
Fig. I. Structures of Co(BCA) (left) and C'o(Py) (rijfAr).
1.0
t
0.01
0.001
50 10O 250
500
Drug Concentration,
uM
Fig. 2. Survival of EMT6 mouse mammary tumor cells treated with various
concentrations of Co(BCA) for 1 h under normally oxygenated conditions (•)or
hypoxic conditions (O) or treated with various concentrations of Co(Py) for 1 h
under normally oxygenated conditions (•)or hypoxic conditions (C). The data
are presented as means ±SE (bars) for three independent experiments.
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ANTITUMOR Co(III) MUSTARD COMPLEX
oxygenated or Hypoxie cells (data not shown).
The cytotoxicity of both Co(BCA) and Co(Py) was increased
when normally oxygenated EMT6 cells were exposed to the
drugs at the clinically relevant hyperthermic temperature of
42°C(Fig. 3). The hyperthermia treatment itself resulted in a
surviving fraction of about 0.65. Hyperthermia had a dosemodifying effect on the cytotoxicity Co(BCA); that is, there was
an increase in the slope of the killing curve produced by
Co(BCA) when the 1-h drug exposure was conducted under
hyperthermic conditions. At a drug concentration of 100 //M
Co(BCA), there was about a 7-fold increase in cytotoxicity at
42°Ccompared with 37°C,after correcting for 42°Cx l h
lethality. On the other hand, the cytotoxicity of Co(Py) and
hyperthermia appeared to be mainly additive. There was about
a 1.8-fold increase in the cytotoxicity of Co(Py) in the presence
of hyperthermia (42°C,1 h) over the entire concentration range
of Co(Py) examined.
Radiation survival curves for EMT6 cells in vitro in the
presence and absence of the cobalt complexes are shown in Fig.
4. These results are drawn corrected for cytotoxicity of drug
alone. The concentration of Co(BCA) and Co(Py) used for
these radiation studies was 100 /J.Mand the drugs were present
for l h prior to and during radiation delivery. Co(BCA) was an
0.001
so too
250
Drug Concentration,
gM
Fig. 3. Survival of EMT6 mouse mammary tumor cells treated with various
concentrations of Co(BCA) for l h under normally oxygenated conditions at 37*C
(•)or 42"C (O) or treated with various concentrations of Co(Py) for l h under
normally oxygenated conditions at 37'C (•)or 42°C(D). The data are presented
as means ±SE (bars) for three independent experiments.
O.OO01
20
10
X-Ray Dose, Qray
20
Fig. 4. Radiation survival of EMT6 mouse mammary tumor cells in the
presence of Co(BCA) or Co(Py). •.no drug, normally oxygenated cells; O, no
drug, hypoxic cells: •100 /IM drug, normally oxygenated cells; D, 100 MMdrug,
hypoxic cells. The data are presented as means ±SE (bars) for three independent
experiments and are corrected for cytotoxicity of drug alone.
effective radiosensitizer of hypoxic EMT6 cells, resulting in a
dose-modifying factor of about 2.40. In contrast, Co(Py) was
not an effective radiosensitizer. The presence of 100 /¿M
Co(Py)
did not significantly alter the slope of the radiation survival
curve of hypoxic EMT6 cells. Neither Co(BCA) or Co(Py) had
any significant effect on the radiation survival of normally
oxygenated EMT6 cells.
As shown in Fig. 5, the SCC-25/HN2 nitrogen mustardresistant subline of the SCC-25 human squamous carcinoma
cell line is approximately 9-fold resistant to nitrogen mustard
at a level of 50% cell kill. Co(BCA) was less toxic toward the
SCC-25 and SCC-25/HN2 cell lines than toward the EMT6
murine cell line. The drug concentration which resulted in 1
log of cell killing by Co(BCA) upon exposure to the drug for 1
h was about 200 MMin the SCC-25 cell line and about 280 fiM
in the SCC-25/HN2 cell line. Therefore, the SCC-25/HN2 cell
line was only about 1.27-fold resistant to Co(BCA) at a level of
90% cell kill, compared to the SCC-25 cell line. The cytotoxicity
of Co(Py) in these human tumor cell lines was somewhat less
than that of Co(BCA), as was the case in EMT6 cells. Exposure
to a concentration of about 465 pM Co(Py) for l h resulted in
1 log of cell killing in the SCC-25 cell line and exposure to a
concentration of about 490 ^M for l h produced the same level
of cell killing in the SCC-25/HN2 cell line. As expected,
therefore, there was no significant difference in the sensitivity
of these two cell lines to Co(Py). BCA is the mustard moiety
present in the Co(BCA) complex. The SCC-25/HN2 cell line
was about 2-fold more resistant to the cytotoxic actions of BCA
than was the SCC-25 cell line. The concentrations of BCA
which resulted in 1 log of cell killing in each cell line were
about 140 and 280 Õ/Min the SCC-25 and SCC-25/HN2 cell
lines, respectively.
The in vivo antitumor activity of the cobalt complexes was
assessed in L1210 leukemia (Table 1). LI210 cells (IO6) were
implanted i.p. in DBA mice on day 0. Treatment was begun on
day 1 and the drugs were administered daily for 5 days.
Co(BCA) was administered over a wide dosage range and was
highly effective against this tumor at doses from 5 to 50 mg/kg
daily for 5 days, where mean survivals of >60 days were
produced. The antitumor activity of Co(BCA) decreased at
doses of 1 mg/kg and less and it was toxic at doses of 100 mg/
kg and greater. Co(Py) was ineffective at a dose of 5 mg/kg and
showed moderate activity at doses of 10 and 50 mg/kg, but
there were no 60-day survivors in any groups of animals treated
with Co(Py). Nor-nitrogen mustard (BCA) was most effective
at a dose of 50 mg/kg but was not nearly as successful as
Co(BCA) and appeared to have a much steeper dose-response
curve in this tumor system than did Co(BCA) or Co(Py).
Using a similar experimental design, tumor growth delay
studies were conducted in the FSallC fibrosarcoma (Table 2).
Treatment was begun when the tumors were about 100 mm3 in
volume and the drugs were administered daily for 5 days.
Co(BCA) treatment resulted in measurable growth delays in
the FSallC fibrosarcoma over the dosage range examined, from
10 to 75 mg/kg. Tumor growth delay continued to increase
with increasing dose of the drug. At 75 mg/kg, Co(BCA)
produced a growth delay of about 9.4 days. Co(Py) was only
minimally effective against the FSallC fibrosarcoma at a dose
of 50 mg/kg and at that dose was about 2.8-fold less effective
than Co(BCA).
DISCUSSION
Complexes of a wide variety of metals have undergone preclinical testing as anticancer agents (1-3). Some of these new
6973
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ANTITUMOR Co(III) MUSTARD COMPLEX
1.0
Fig. 5. Survival of SCC-25 (•)and SCC25/HN2 (O) human squamous carcinoma cells
exposed to various concentrations of nitrogen
mustard, Co(BCA), Co(Py), or BCA. The data
are presented as means ±SE (ears) for three
independent experiments.
0.01
100
260
600
100
250
500
100
250
600
Drug Concentration, MM
Table 1 Survival of mice bearing LI 210 leukemia treated with Co(BCA), Co(Py),
or BCA
Controls from four experiments survived 8.4 ±0.6 days. Tumor cells (10*)
were implanted i.p. on day 0. Drugs were administered on days 1-5.
the study contained coordinated nitro ligands, the presence of
nitro ligands on the complex was not a requirement for radi
osensitizing activity. All of the trinitrotiamine-containing
com
plexes
were
very
effective
radiosensitizers,
whether
the
amine
dose
was NH3, CH.,NH2, or the chelating ligand diethyltriamine.
DrugCo(BCA)Co(Py)BCADaily
(mg/kg)250100SO2510510.5O.I1005010510050105Survival
(days)4.4
Within the nitroamine series, increasing the number of nitro
1.015.6
±
ligands led to increased radiosensitizer activity. Co(BCA) is a
1.6>60>60>60>6044.5
±
Co(III) complex containing a nitroligand and a ligand capable
of bifunctional alkylation upon release from the complex. The
action of alkylating moiety in enhancing the cytotoxicity of this
2.422.3
±
new complex is evident in its increased cytotoxicity toward both
1.718.9
±
the EMT6 murine tumor cell line and the SCC-25 and SCC1.86.7
±
25/HN2 human tumor cell lines, as compared to the pyridinecontaining analogue. The dose-modifying effect of hyperther0.529.0
±
2.727.6
±
mia on the cytotoxicity of this complex is similar to patterns
2.48.9
±
observed with other alkylating agents and hyperthermia.
1.112.7
±
Whether the increase in cytotoxicity of Co(BCA) at elevated
1.538.8
±
temperature is due to increased intracellular drug levels, in
2.917.8
±
creased reactivity with DNA, or hyperthermia-induced inhibi
1.810.1
±
±1.4T/C"Toxic1.8>7.1>7.1>7.1>7.15.32.62.2Toxic3.43.31.061.54.62.11.2
tion of DNA repair remains to be defined for this drug, as for
* Survival of treated/survival of control.
most other drugs which interact with hyperthermia (33).
The Co(BCA) complex was an effective radiosensitizer of
hypoxic EMT6 cells, with efficacy similar to that of cis-dinitroTable 2 Growth delay of the FSal 1Cfibrosarcoma produced by treatment with
tetrammine-cobalt(III).
The lack of radiosensitizing effect by
Co(BCA) or Co(Py)
Drugs were administered i.p. daily on days 7-11 after tumor cell implantation.
the Co(Py) complex may be due to a failure of the complex to
growth delay
reach a position near enough to the DNA to allow the Co(III)
DrugCo(BCA)Co(Py)Dose(mg/kg)10255075255075Tumor
(days)3.1
moiety to participate in transfer functions. The particular con
1.04.4
±
figuration of this molecular may, itself, inhibit electron trans
1.28.2
±
fers.
1.69.4
±
Nitrogen mustard is transported into cells via the choline
1.51.2
±
transport system. The resistance of cells in culture to nitrogen
±0.72.9
mustard has often been attributed to a decrease in the transport
1.1Toxic
±
of the drug into the cells (34). Co(BCA), Co(Py), and BCA may
enter cells primarily by passive diffusion and, consequently,
alteration in the choline transport system would not effect
metal complexes, like the classical inorganic anticancer agent
cellular sensitivity to these drugs. Co(BCA), therefore, would
cis-diamminedichloroplatinum(II),
have the potential to form
be expected to be a mustard-containing antitumor agent which
coordination bonds with cellular targets and would generally be is not cross-resistant with nitrogen mustard in the SCC-25/
classified an antitumor alkylating agents (1-4). Others, such as HN2 subline, as was essentially found in these studies.
the chiral Co(III) Ã-rá-phenanthroline complexes, bind tightly
Co(BCA) showed an unusually broad dosage range of activity
and site-specifically to DNA (29-31). Some of these site-spe
against both the LI210 leukemia and the FSal 1C fibrosarcoma.
cific binding agents can be activated oxidatively to cleave the Co(BCA) was more efficacious and less toxic than Co(Py) in
both murine tumor systems. Co(BCA) may be regarded as the
DNA (32).
lead complex for a new class of antitumor agents with both a
The precise properties which result in optimal radiosensitizbifunctional organic alkylating capability and a metal compo
ing ability in metal complexes are not known. We have previ
ously examined the radiosensitizing potential of a series of 12 nent capable of radiosensization.
Co(III) complexes, ranging in structure from hexanitro-Co(III)
to hexammine-Co(III), in vitro (12). At the relatively low drug
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6975
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1990 American Association for Cancer Research.
Cytotoxicity, Radiosensitization, Antitumor Activity, and
Interaction with Hyperthermia of a Co(III) Mustard Complex
Beverly A. Teicher, Michael J. Abrams, Kristina W. Rosbe, et al.
Cancer Res 1990;50:6971-6975.
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