U.S. patent application number 10/734570 was filed with the patent office on 2004-09-16 for method of reducing toxicity of anticancer agents.
Invention is credited to Cao, Shousong, Durrani, Farukh, Rustum, Youcef M..
Application Number | 20040180099 10/734570 |
Document ID | / |
Family ID | 32468782 |
Filed Date | 2004-09-16 |
United States Patent
Application |
20040180099 |
Kind Code |
A1 |
Rustum, Youcef M. ; et
al. |
September 16, 2004 |
Method of reducing toxicity of anticancer agents
Abstract
The present invention discloses a method for reducing the
toxicity of anti-cancer agents oxaliplatin and doxorubicin. The
method comprises administering to an individual, in need of such a
treatment, the anti-cancer agent and a selenium compound. The
selenium compounds may be administered before, during or after
administration of the anti-cancer agent.
Inventors: |
Rustum, Youcef M.; (Amherst,
NY) ; Cao, Shousong; (East Amherst, NY) ;
Durrani, Farukh; (Snyder, NY) |
Correspondence
Address: |
HODGSON RUSS LLP
ONE M & T PLAZA
SUITE 2000
BUFFALO
NY
14203-2391
US
|
Family ID: |
32468782 |
Appl. No.: |
10/734570 |
Filed: |
December 12, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10734570 |
Dec 12, 2003 |
|
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10315721 |
Dec 10, 2002 |
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Current U.S.
Class: |
424/702 ; 514/34;
514/492; 514/561 |
Current CPC
Class: |
A61K 31/7072 20130101;
A61P 35/00 20180101; A61K 31/4745 20130101; A61K 31/198 20130101;
A61K 45/06 20130101 |
Class at
Publication: |
424/702 ;
514/034; 514/561; 514/492 |
International
Class: |
A61K 033/04; A61K
031/704; A61K 031/198; A61K 031/28 |
Claims
1. A method for reducing the in vivo toxicity of an anticancer
agent selected from the group consisting of oxaliplatin and
doxorubicin comprising the steps of administering to an individual
in need of treatment a therapeutically effective dose of the
anticancer agent and a selenium compound wherein the toxicity
induced by the anticancer agent is less than the toxicity induced
in the absence of administered selenium compound.
2. The method of claim 1, wherein the anticancer agent is
doxorubicin.
3. The method of claim 1, wherein the anticancer agent is
oxaliplatin.
4. The method of claim 1, wherein the selenium compound is
seleno-L-methionine.
5. The method of claim 1, wherein the selenium compound is
methylselenocysteine.
6. The method of claim 1, wherein the selenium compound is
administered at a time selected from the group consisting of prior
to administration of the anticancer agent, during administration of
the anticancer agent, following administration of the anticancer
agent and a combination thereof.
7. A method for using an anticancer agent selected from the group
consisting of oxaliplatin and doxorubicin at a higher than
therapeutic dose comprising the steps of administering to an
individual in need of treatment a higher than therapeutic dose of
the anticancer agent and a selenium compound, wherein the toxicity
of the anticancer agent is reduced with the administration of the
selenium compound.
8. The method of claim 7, wherein the anticancer agent is
doxorubicin.
9. The method of claim 7, wherein the anticancer agent is
oxaliplatin.
10. The method of claim 7, wherein the selenium compound is
seleno-L-methionine.
11. The method of claim 7, wherein the selenium compound is
methylselenocysteine.
12. The method of claim 7, wherein the selenium compound is
administered at a time selected from the group consisting of prior
to administration of the anticancer agent, during administration of
the anticancer agent, following administration of the anticancer
agent and a combination thereof.
Description
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 10/315,721 filed on Dec. 10, 2002, the
disclosure of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates generally to the field of cancer
therapy and more particularly to a method for reducing undesirable
toxicity of chemotherapeutic agents.
DESCRIPTION OF RELATED ART
[0003] Chemotherapy is now a recognized and widely used modality of
cancer treatment. Depending upon the type of cancer, chemotherapy
is often the primary course of treatment. For example, chemotherapy
is widely used either alone or in combination with other treatments
such as radiation treatment for a variety of cancers including
cancer of the ovary, testis, breast, bladder, colon, head and neck
as well as leukemia, lymphomas, sarcomas, melanomas, lung,
prostate, ovary and others.
[0004] Chemotherapeutic agents are broadly classified into a number
of groups. The majority of anticancer drugs act as cytotoxic drugs.
The classification of these drugs into groups is mechanism based.
While chemotherapeutic agents have proven extremely useful in the
treatment of cancer, nearly all of them are associated with
significant toxic effects because of their potential to kill
cancerous as well as healthy cells. The toxicity associated with
anticancer drugs often forces discontinuation of treatment which
may negatively impact the prognosis of patient's condition and
clinical outcome and result in compromising the quality of
life.
[0005] Some recent studies have attempted to address the issue of
toxicity of anticancer agents (Steifel et al., 1999, WO 99/64018;
Chen et al., 1986, J. Nurtition, 116(12):2453-2465; Dobric et al.,
1998, J. Environ. Pathol. Toxicol Oncol., 17:291-299. However,
these studies only describe the effects of selenium on in vitro
toxicity of certain anticancer agents. Given the inherent
difficulties of extrapolating the in vitro studies to treatment
regimens for cancer patients, it is not clear whether the in vivo
toxicity of anticancer agents can be reduced. Some in vivo studies
(Van Vleet et al., 1980, Am. J. Pathol., 99:13-42; Van Vleet et
al., Am. J. Vet Res., 1980, 41(5):691-699; Van Vleet et al., Am. J.
Vet Res., 1981, 42(7):1153-1159 indicate that selenium failed to
alter the in vivo toxicity induced by adriamycin. Accordingly,
currently there is no effective way to reduce the toxicity of
anticancer agents without compromising their efficacy. Thus there
is a need in the field of cancer chemotherapy to identify methods
and compositions by which the toxic side effects can be reduced
without compromising the anticancer efficacy.
SUMMARY OF THE INVENTION
[0006] In the present invention it was observed that administration
of selenium compounds reduces the toxicity of anticancer agents.
Data is presented for in vivo studies in two animal models.
[0007] The present invention discloses a method for reducing the
toxicity of anticancer agents. The method comprises administering
to an individual, in need of treatment, an anti-tumor agent and a
selenium compound. The selenium compounds may be administered
before, during or after administration of the anti-cancer agent. In
one embodiment, the selenium compound is administered prior to
chemotherapy and may be continued during and after the
chemotherapy.
BRIEF DESCRIPTION OF THE FIGURES
[0008] FIG. 1 is a representation of the effect of selenium on the
toxicity of irinotecan (CPT-11) in nude mice. Irinotecan was
administered by i.v. push once a week for 4 weeks and
methylselenocysteine (MSC) by oral route (p.o.) daily for 42 days
with the first dose administered 21 days prior to the
administration of irinotecan. The data are combined from at least
three independent experiments with five (5) animals per
experiment.
[0009] FIG. 2 is a representation of the effect of selenium
compounds on the toxicity of irinotecan in rats. Irinotecan was
administered by intravenous (i.v.) push once for three (3) days and
MSC by p.o. at 1 mg/kg/rat daily for 18 days with the first dose
being given at 14 days before irinotecan treatment. The data are
combined from 2-5 independent experiments with four (4) animals for
each experiment.
[0010] FIG. 3 is a representation of the effect of selenium on
survival rate of nude mice upon administration of anticancer
agents. Data are presented for cisplatin (CDDP), taxol,
5-Fluorouracil (FU) and irinotecan with or without selenium
treatment.
[0011] FIG. 4 is a representation of the effect of two selenium
compounds on the survival rate in nude mice upon administration of
irinotecan. Irinotecan was administered by i.v. push once a week
for 4 weeks, MSC and seleno-L-methionine (SLM) were given p.o.
daily for 28 days with the first dose being administered 7 days
before irinotecan treatment. Five mice were used for each
experiment group for irinotecan +MSC, four experiments were done
with 100 mg/kg and 200 mg/kg, two experiments with 300 mg/kg, two
experiments for irinotecan +SLM.
[0012] FIG. 5 is a representation of the dose effect of MSC in
protection of irinotecan induced toxicity in nude mice. Irinotecan
was administered by i.v. push once a week for 4 weeks and MSC was
given once a week for 28 days with the first dose starting 7 days
before irinotecan treatment. Data are from two independent
experiments with 2 groups of 10 mice each.
[0013] FIG. 6 is a table representing the effect of MSC on the
hematological changes induced by irinotecan. * indicates mg/mouse;
** indicates mg/kg; three mice for each group with duplicate
samples (6 samples). WBC: white blood cell (THSN/CU MM); RBC: red
blood cell (Mill/CU MM); HGB: hemoglobin (Gram/DL); HCT:
haematocrit (%); MCV: mean corpuscular volume (CU Microns); MCH:
mean corpuscular hemoglobin (PICO Grams); MCHC: mean corpuscular
hemoglobin concentration (%); PLT: platelets (THSN/CU MM).
[0014] FIGS. 7A and 7B are representations of the effect of
selenium on the survival rate of nude mice upon administration of
doxorubicin (7A) or oxaliplatin (7B). Doxorubicin was administered
by a single i.v. injection and oxaliplatin by i.v. push
weekly.times.4. MSC as administered at a dose of 0.2 mg/mouse/day
p.o. daily for 7 days before drug treatment and continued 7 days
after doxorubicin and 21 days after oxaliplatin treatment. Data is
shown as percent of total survivors for doxorubicin and
oxaliplatin, either alone or in combination with MSC as a function
of time.
[0015] FIG. 8 is a representation of the effect of selenium
treatment on the survival rate in nude mice upon administration of
oxaliplatin or doxorubicin. Doxorubicin was administered by a
single i.v. injection and oxaliplatin by i.v. push weekly.times.4.
MSC was administered at a dose of 0.2 mg/mouse/day p.o. daily for 7
days before drug treatment and continued 7 days after doxorubicin
and 21 days after oxaliplatin treatment. Data is shown as percent
of total survivors for doxorubicin and oxaliplatin, either alone or
in combination with MSC.
[0016] FIG. 9 is a representation of the effect of selenium on the
survival rate of rats upon administration of oxaliplatin.
Oxaliplatin was administered by a single i.v. injection and MSC
0.75 mg/rat/day p.o. daily for 21 days and the first dose was
started 14 days before oxaliplatin treatment. Eight rats were used
in each group. Data is shown as percent of total survivors for
oxaliplatin alone or in combination with MSC.
[0017] FIG. 10 is another representation of the effect of selenium
on the survival rate of rats after administration of oxaliplatin.
Oxaliplatin was administered by a single i.v. injection and MSC
(0.75 mg/kg/rat/day) was given p.o. daily for 21 days and the first
dose was started 14 days before oxaliplatin treatment. Eight rats
were used in each group. Data is shown as percent of survivors as a
function of time.
[0018] FIG. 11 is a table showing hematological changes induced by
oxaliplatin alone or in combination with MSC in nude mice. *
indicates mg/mouse (p.o. daily.times.12); ** indicates mg/kg
(i.v..times.1); For the combination, MSC was given 7 days before
oxliplatin. Five mice were used in each group. WBC: white blood
cell (THSN/CU MM); RBC: red blood cell (Mill/CU MM); HGB:
hemoglobin (Gram/DL); HCT: haematocrit (%); MCV: mean corpuscular
volume (CU Microns); MCH: mean corpuscular hemoglobin (PICO Grams);
MCHC: mean corpuscular hemoglobin concentration (%); PLT: platelets
(THSN/CU MM).
[0019] FIG. 12 is a table showing white blood cells, neutrophils
and platelets changes induced by oxaliplatin alone or in
combination with MSC in nude mice.
[0020] FIG. 13 is a table showing differential WBC count in nude
mice on day 5 after treatment with oxaliplatin alone or in
combination with MSC in nude mice.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The term "therapeutic dose" as used herein means the dosage
of a therapeutic agent that is acceptable for use clinically with
respect to its toxicity without the co-administration of selenium
compounds.
[0022] The present invention discloses a method for reducing the
toxicity of anticancer agents while maintaining or enhancing their
efficacy. The method comprises administering to an individual, in
need of such a treatment, one or more anticancer agents and one or
more selenium compounds. The selenium compounds may be administered
before, during or after administration of the anticancer agent. By
combining chemotherapy with the administration of selenium
compounds, the toxicity of the chemotherapeutic agent can be
decreased.
[0023] This invention is useful for reducing the toxicity of
anticancer agents including fluoropyrimidines, pyrimidine
nucleosides, purines, platinum analogues, antroacyclines,
podophyllotoxins, camptothecins, hormones and hormone analogues,
enzymes, proteins and antibodies, vinca alkaloids, taxanes. The
anti-cancer agents for the present invention generally fall into
one or more of the following functional categories: antihormones,
antifolates, antimicrotubule agents, alkylating agents,
antimetabolites, antibiotics, topoisomerase inhibitors and
antivirals.
[0024] Selenium compounds useful for the present invention can be
from either organic or inorganic forms. It is preferable to use
selenium from organic forms since these are known to be less toxic.
Examples of useful selenium compounds from organic forms include
methylselenocysteine (MSC) and seleno-L-methionine (SLM). The doses
of selenium compounds are in the range of about 200 .mu.g/person to
about 3.6 mg/person and maybe administered daily for 1 year or
longer. It has been reported that up to 800 .mu.g/patient is
generally considered to be safe without associated toxicity.
[0025] The present invention comprises the steps of combining
chemotherapy with the administration of selenium. One or more
chemotherapeutic agents may be used accordingly to the criteria
well known in the art of cancer chemotherapeutics. The dosage and
administrative regimens of the chemotherapeutics are well within
the purview of those skilled in the art. Selenium administration
can be initiated before the start of chemotherapy, during
chemotherapy or after cessation of chemotherapy. If initiated
before the start of chemotherapy, selenium administration can be
continued during the chemotherapy and after cessation of
chemotherapy. Similarly, if initiated during chemotherapy, selenium
administration can continue after cessation of chemotherapy.
[0026] While the present method for reducing toxicity is applicable
for any chemotherapeutic agent some exemplary ones are irinotecan,
FU, taxol, cisplatin adriamycin, oxaliplatin, cyclophosphamide, and
EGF and VGF inhibitors. In addition, the present invention can also
be used for reducing the toxicity associated with other anticancer
therapies such as radiation treatment.
[0027] To demonstrate the effect of selenium in reducing the toxic
effect of chemotherapeutic agents, two animal models were used.
Thus, studies were carried out in normal nude mice and rats as well
as in tumor bearing nude mice. It should be noted that while
previous studies have reported an effect of selenium on reducing
toxicity (such as cardiotoxicity) of some anticancer agents in
vitro, there has been no demonstration of an effect of selenium on
the in vivo toxicity of these agents. Further, the in vitro studies
also do not permit an assessment of the effect of selenium on the
efficacy of anticancer agents.
[0028] In one embodiment of the invention, it was determined that
methylselenocysteine (MSC) and seleno-L-methionine (SLM) are
effective agents in protecting from toxic and lethal doses of five
classes of clinically approved chemotherapeutic agents; namely
irinotecan (topoisomere I inhibitor); doxorubicin (topoisomerase II
inhibitor), FU (DNA synthetic inhibitor); taxol (microtubule
inhibitor) and cisplatin and oxaliplatin (DNA alkalating agents).
The two selenium containing compounds were evaluated in two host
systems (mice and rats) against agents representing five classes of
anticancer drugs. The in vivo effects were observed using non-toxic
doses of the selenium containing compounds (about 0.2 mg/mouse/day
or lower).
[0029] When selenium is administered to an individual in need of
therapy for cancer to reduce the toxicity, the dose of the
chemotherapeutic agent (or radiation dose) can be increased so as
to have greater efficacy.
[0030] The following examples are provided below to illustrate the
present invention. These examples are intended to be illustrative
and are not to be construed as limiting in any way.
EXAMPLE 1
[0031] Evaluation of the effects of selenium on the in vivo
toxicity of irinotecan in normal nude mice. This embodiment
demonstrates that selenium reduces toxocity induced by irinotecan.
To illustrate this embodiment, nude mice were administered 42
single, daily oral doses of 0.2 mg/mouse of MSC. After 21 days,
irinotecan was administered intravenously in doses of 50, 100, 200
and 300 mg/kg/wkx4. The data in FIG. 1 is a summary of the results
from at least three separate experiments with five (5) mice per
group obtained with irinotecan alone and in combination with the 42
daily oral administrations of MSC.
[0032] The results can be summarized as follows: Amongst the
concentration studies, the maximum tolerated dose (MTD) of 100
mg/kg/wk irinotecan resulted in less than 20% weight loss and no
lethality (100% of animal survived treatment). The addition of MSC
to this regimen results in decrease in overall body weight loss,
signifying improved animal well being. With the MSC treatment of
this group, the weight loss was less than what was observed with
irinotecan alone. In contrast with 200 mg/kg/wkx4 doses and 300
mg/kg/wkx4 of irinotecan representing twice and three times the
MTD's, MSC provided 100% and 80% protection, respectively. Thus,
with 200 mg/kg/wkx4 doses of irinotecan, 55% of animals died by the
end of treatment while none of the animals died (100% survived)
when treated with MSC. These data demonstrate that selenium
protects against lethal doses of irinotecan.
EXAMPLE 2
[0033] Evaluation of the effects of MSC on the toxicity of
irinotecan (CPT-11) in normal rats. To demonstrate the effects of
MSC on irinotecan induced toxicity in another species, rats were
administered orally with 1 mg/kg/rat daily for 18 days with the
first dose administered 14 days prior to irinotecan treatment. In
the treated group, irinotecan was administered by i.v. push once a
day for three (3) days. The results are shown in FIG. 2.
[0034] The data in FIG. 2 is a summary of the survival results
obtained in two experiments using four (4) rats per group
demonstrating the protective effects of MSC. A protective effect of
MSC was observed when the concentration of irinotecan was increased
to 200 mg/kg/day for three (3) days (twice the MTD), wherein all
the animals in the group administered irinotecan alone died, only
50% of the animals died in the group administered MSC plus
irinotecan.
EXAMPLE 3
[0035] Evaluation of the effects of MSC on the toxicity of
irinotecan in tumor bearing animals. To demonstrate the effect of
MSC on the antitumor activity of chemotherapy, nude mice bearing
transplantable squamous cell carcinoma of the head and neck (A253)
were transplanted subcutaneously (s.c.) with tumor fragments and
drug treatments were initiated when tumor sizes approach about 200
mg in size. Irinotecan was administered at 100 times maximum
tolerated dose (MTD), 200 or 300 mg/kg/wk for four (4) weeks
representing two (2) and three (3) times the MTD, respectively in
the presence or absence of MSC 0.2 mg/mouse/day. MSC was
administered for 42 days and irinotecan was administered after the
first 21 days of the MSC treatment. The results are presented in
Table 1.
1TABLE 1 Antitumor Activity of Irinotecan by Methylselenocysteine
(MSC) in Xenographts Bearing Transplantable Sequamous Cell
Carcinoma of the head and neck (A253) Response Rate (%) Treatment*
PR CR Survivors (%) Irinotecan (100) 20 20 100 Irinotecan (100) +
MSC 40 60 100 Irinotecan (200) NA.sup..dagger. NA.sup..dagger. 45
Irinotecan (200) + MSC 20 80 100 Irinotecan (300) NA.sup..dagger.
NA.sup..dagger. 0 Irinotecan (300) + MSC 20 80 80 *Irinotecan
mg/kg/wk .times. 4 (i.v.); MSC, 0.2 mg/mouse/d .times. 42 (p.o.)
with MSC administered for 21 days prior to treatment with
Irinotecan. .sup..dagger.NA, response was not tabulated since death
occurred in 65 to 100 of the animals during treatment. The
surviving animals did not achieve CR.
[0036] The data in Table 1 represents a summary of the therapeutic
selectivity of the combination of irinotecan with MSC. The data
indicate that MSC protection against irinotecan induced toxicity
was selective resulting in increased survivors (protection) of
animals treated with lethal doses of irinotecan (200 mg/kg). Under
the condition of selective protection, the antitumor activity of
irinotecan was significantly increased from 20% complete tumor
response (CR) with irinotecan alone to 80% CR in combination with
MSC.
EXAMPLE 4
[0037] Evaluation of effects of selenium on the toxicity of
Chemotherapeutic agents To demonstrate that the effect of selenium
in reducing toxicity is not limited to irinotecan, the effects of
selenium on toxicity induced by Taxol, FU, and cisplatin was
evaluated in normal nude mice. Except for the weekly schedule of
irinotecan, taxol (75 mg/kg), 5-FU (150 mg/kg) and cisplatin (15
mg/kg) were administered once via the intravenously route. In all
cases drug doses used were toxic and above the maximum tolerated
dose. The results are shown in FIG. 3. For each chemotherapeutic
agent, a protective effect of MSC was observed on the survival rate
of animals. Thus, these data indicate the general applicability of
selenium as modulator of host toxicity induced by chemotherapeutic
agents. It is important to note that chemotherapeutic agents used
herein represent different classes of anticancer drugs, i.e., a
topoisomerase I inhibitor (irinotecan); a DNA synthesized inhibitor
(FU); a microtubule inhibitor (taxol); and a DNA alkalating agent
(cisplatin).
EXAMPLE 5
[0038] Comparative evaluation of MSC and SLM as modulators of
toxicity induced by irinotecan in normal nude mice. To determine if
selenium compounds other than MSC can also provide protective
effects against toxicity induced by chemotherapeutic agents, a
comparative study of MSC and SLM was carried out in nude mice.
Irinotecan was administered by i.v. push once a week for 4 weeks.
MSC and SLM were given p.o. daily for 28 days and the first dose
was administered seven (7) days prior to irinotecan treatment. Each
experimental group had 10 mice each from two (2) independent
experiments. The results are shown in FIG. 4. Using a irinotecan
dose of 200 mg/kg/wkx4, which produced approximately 55% lethality
(45% survivors), MSC and SLM were equally effective in reducing
toxicity. This data indicates the protective effects are not
specific for MSC, but SLM produced similar results.
EXAMPLE 6
[0039] Role of MSC dose in modulating the toxicity of irinotecan.
In order to identify the minimum dose of MSC in the successful
modulation of drug induced toxicities. Studies were carried out in
normal mice treated with different doses of MSC (0.01 to 0.2
mg/mouse/dayx42) in combination with irinotecan (200 mg/kg/wkx4).
The data which are summarized in FIG. 5 indicate that an MSC dose
as low as 0.01 mg/mouse was sufficient to offer complete protection
against lethal doses of irinotecan with no lethality with the
combination. In contrast, irinotecan alone yielded 50% lethality.
Those skilled in the art will recognize that by conducting
experiments as described herein, optimal doses of selenium for
reducing toxicity of other chemotherapeutic agents and other
anticancer modalities can be easily determined.
EXAMPLE 7
[0040] Effects of MSC on the hematologic toxicity induced by
irinotecan in normal nude mice. With the rodent model used in this
invention, the dose limiting toxicity associated with irinotecan in
rats was diarrhea, mouth ulceration and hematologic toxicity, and
in mice primarily hematologic toxicity. MSC was administered 0.2
mg/mouse/day with the first dose administered seven (7) days prior
to irinotecan treatment. Twenty-four (24) hours after the third
weekly dose of irinotecan blood samples were removed and analyzed
for the parameters outlined in FIG. 6. All hematological parameters
were determined by standard methods. As demonstrated in FIG. 2, MSC
offered complete protection in 50% of animals with severe diarrhea
at the 200 mg/kg dose of irinotecan. To identify possible
mechanisms of action of the selenium compounds in reducing the
hematologic toxicity induced by irinotecan, the effects of MSC with
or without irinotecan were investigated on hematological
parameters. The data in FIG. 6 indicates that over 60% reduction in
white blood cells was observed in mice (9.4 to 3.5), i.e.
significant neutropenia was induced by irinotecan at a 200 mg/kg/wk
dose, a dose limiting toxicity similar to what is normally observed
in patients treated with irinotecan. These data demonstrate that
MSC can effectively prevent neutropenia toxicity induced by
irinotecan. Irinotecan, either alone or in combination with MSC had
no significant effect on the other hematologic parameters.
[0041] The data presented herein demonstrate that non-toxic doses
of selenium compounds protect mice against toxicity induced by
irinotecan. As an example, it is demonstrated herein that MSC
offers complete protection against hematologic toxicity induced by
irinotecan (200 mg/kg/wkx4, a dose at which 55% of mice would
normally die of toxicity. Complete protection from irinotecan
induced toxicity was associated with complete protection against
hematologic toxicity.
EXAMPLE 8
[0042] Reversal of renal toxicity induced by Cisplatin (CDDP). The
dose limiting toxicity of therapeutic doses of cisplatin is kidney
toxicity. Studies were performed to identify blood biological
markers modified by CDDP and to evaluate the ability of MSC to
reverse the process. Four groups of six animals each were used. The
first group was untreated rats (control), the second group was
given MSC at 0.75 mg/rat/day for 20 days and samples collected 2
hours after MSC administration on day 20. The third group was
administered CDDP alone at 6 mg/kg by a single
2TABLE 2 Renal function test after CDDP .+-. MSC treatment in rats
Blood Urea Nitrogen Treatment (mg/dl) Creatinine (mg/dl) Control
16.0 .+-. 2.0* 0.32 .+-. 0.04 MSC (0.75) 12.7 .+-. 1.2 0.30 .+-.
0.00 CDDP (6) 147.2 .+-. 103 2.78 .+-. 2.57 CDDP (6) + MSC (0.75)
32.7 .+-. 6.8 0.43 .+-. 0.05 *Mean .+-. SD. CDDP (6 mg/kg) was
administered by a single i.v. push and MSC (0.75 mg/rat) daily for
20 days which start 14 days before CDDP; the animals were
sacrificed on days after CDDP treatment. Six rats for each
group.
[0043] i.v. injection and samples were collected on day 6. The
fourth group was adminstered MSC (0.75 mg/rat/day for 20 days) with
CDDP (6 mg/kg). CDDP was given 14 days after MSC administration and
NSC was given for 6 more days after CDDP administration. Samples
were collected on day 6 after CDDP administration. Blood samples
were collected at postmortem by cardiac puncture. Serum was
obtained from the blood samples and urea nitrogen and creatinine
concentrations were determined by standard methods using
commercially kits (Ortho Clinical Diagnostics).
[0044] The data, shown in Table 2, indicates a dramatic
upregulation of these markers induced by CDDP treatment and return
the level of these markers to approximately control values when MSC
was co-administered with CDDP. This indicates that MSC is highly
effective in reversal of markers associated with kidney toxicity,
namely blood urea nitrogen (BUN) and creatinine. Furthermore,
morphological and structural modifications induced by CDDP in
kidney were not detectable in kidneys of animals treated with MSC
in combination with CDDP.
EXAMPLE 9
[0045] Methylselenocysteine (MSC) is an effective modulator of the
toxicity of anticancer drugs, doxorubicin and oxaliplatin in normal
nude mice. To illustrate this embodiment, nude mice were
administered doxorubicin or oxaliplatin either alone or in
combination with MSC (0.2 mg/mouse/d). The results are shown in
FIGS. 7A and 7B. The data indicate that 15 mg/kg doxorubicin dose
was highly toxic since 100% of the animals died within 14 days. In
contrast, in combination with MSC, 80% of the animals survived
(FIG. 7A). With oxaliplatin (FIG. 7B), 15 mg/kg was toxic to 80% of
animals and MSC offered a significant protection.
[0046] Doxorubicin at 15 mg/kg.times.1 is toxic in 100% of the
animals treated (0% survival, FIG. 8). In contrast doxorubicin in
combination with non-toxic dose and indicated schedule of MSC (0.2
mg/mouse/d.times.14 with the first dose administered seven days
prior to doxorubicin i.v. administration) offered complete
potentiation for drug induced toxicity with 100% of animal
surviving drug treatment without lethality (FIG. 8).
[0047] With oxaliplatin, a new platinum drug that has been approved
by the Food and Drug Administration (FDA) in patients with advanced
colorectal cancer, a dose of 15 mg/kg/wk.times.4 was toxic to 80%
of animals treated (20% survivors). However, in combination with
non-toxic dose and schedule of MSC (0.2 mg/mouse/d.times.28 days
with the first dose was administered seven days prior to
oxaliplatin and continued for 21 days during drug treatment)
complete protection for drug induced toxicity was observed (FIG.
8).
EXAMPLE 10
[0048] Methylselenocysteine (MSC) is an effective modulator of the
toxicity of anticancer drugs, doxorubicin and oxaliplatin in rats.
To demonstrate that a similar protective effect of selenium
toxicity could also be observed in another animal model, Fisher
rats were administered doxorubicin or oxaliplatin either alone or
in combination with MSC (0.75 mg/rat/d). The results are shown in
FIG. 9. The data indicate that oxaliplatin at 20 and 25 mg/kg doses
were toxic in that 100% lethality was observed within 14 days after
oxaliplatin treatment. In contrast, with 25 mg/kg oxaliplatin in
combination with MSC, 50% of treated animals survived with no
evidence of long term toxicity. Further, MSC was highly effective
(100% survival) in animals treated with 20 mg/kg. Thus, MSC offered
complete protection from toxic doses of oxaliplatin (20 mg/kg).
Also, of interest, oxaliplatin at 25 mg/kg induced diarrhea in 100%
of treated rats (no diarrhea observed at 20 mg/kg) while no
diarrhea was observed when MSC was combined with oxaliplatin at 25
mg/kg. These data demonstrate MSC is effective in protection of
drug induced diarrhea also.
[0049] The data in FIG. 10 further demonstrates that MSC is an
effective agent in protecting against oxaliplatin induced toxicity.
While 20 mg/kg oxaliplatin was highly toxic (0% survivors) in
normal Fisher rats, complete protection was observed when these
toxic doses where combined with non-toxic dose and schedule of MSC
(0.75 mg/rat/d) (FIG. 9). Thus, MSC is a highly effective agent in
protecting individuals from doxorubicin and oxaliplatin induced
toxicity.
EXAMPLE 11
[0050] MSC protects against hemotologic toxicity induced by
oxaliplatin in nude mice. Nude mice were administered oxaliplatin
alone (15 mg/kg (i.v..times.1)) or in combination with MSC (0.2
mg/mouse (p.o. daily.times.12)). For the combination, MSC was given
7 days before oxliplatin. The results are shown in FIGS. 11-13. The
data in FIGS. 11-13 is a summary of the effects of oxaliplatin
alone and in combination with MSC on the hemotologic toxicity
induced in normal nude mice. The data in Figure 11 indicate that
while oxaliplatin induced significant drop in blood count (WBC)
from 2.69 to 0.90, complete restoration of WBC count to control was
observed when oxaliplatin was combined with MSC. Similar effect and
protection was offered against platelet counts (PLT). Oxaliplatin
alone and in combination with MSC had no significant effect on the
other parameters shown in the table in FIG. 1.
[0051] The data in FIG. 12 indicates that the drop in blood counts
was specific for neutrophilis and platelets. These toxicities were
also observed in the clinical trials following treatment with
oxaliplatin. The data in FIG. 13 is a summary of differential WBC
counts indicating that MSC protects against neutropenia, monocyte
and leucocyte toxicity induced by oxaliplatin in mice.
[0052] A summary of the maximum tolerated doses of oxaliplatin and
doxorubicin alone and in combination with MSC is presented in Table
3 below. The data indicate that the MTD of drugs is higher when
combined with MSC.
3 TABLE 3 MTD (mg/kg) Drug MSC Rats Mice Doxorubicin - ND 10
Doxorubicin + ND 12.5 Oxaliplatin - 15 7.5 Oxaliplatin + 20 12.5 ND
= not determined
[0053] In summary, the data presented here indicate that severe
toxicity experienced with administration of anticancer agents is
reduced by administration of selenium compounds offering the
potential of the use of selenium containing compounds as a
modulator of the therapeutic selectivity and efficacy of broad
spectrum and clinically active chemotherapeutic agents. The use of
these agents as a modulator of toxicity and antitumor activity of
broad spectrum of anticancer agent is unexpected. Thus, this
approach will have a significant impact on quality of life and
survival of cancer patients treated with chemotherapy.
* * * * *