NZ732228B2 - Telomerase mediated telomere altering compounds - Google Patents
Telomerase mediated telomere altering compounds Download PDFInfo
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- NZ732228B2 NZ732228B2 NZ732228A NZ73222814A NZ732228B2 NZ 732228 B2 NZ732228 B2 NZ 732228B2 NZ 732228 A NZ732228 A NZ 732228A NZ 73222814 A NZ73222814 A NZ 73222814A NZ 732228 B2 NZ732228 B2 NZ 732228B2
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- telomerase
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Abstract
The present disclosure is directed toward pharmaceutical compositions and methods of using 6-mercaptopurine ribosides and analogues thereof for the treatment of cancer and other hyperproliferative diseases. The described compounds can be converted into telomere substrates in vivo and can be recognized by telomerase for incorporation into telomeres of telomerase active cells, leading to induction of cell death of the telomerase active cells. ed by telomerase for incorporation into telomeres of telomerase active cells, leading to induction of cell death of the telomerase active cells.
Description
DESCRIPTION
TELOMERASE MEDIATED TELOMERE ALTERING COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of New Zealand patent application 713498, which
is the national phase entry in New Zealand of PCT international application
(published as ), and claims the benefit of U.S. United
States Provisional Application Serial No. 61/809,575 filed on April 8, 2013, the contents all
of which are hereby incorporated by reference in their entirety.
BACKGROUND
1. Field of the Invention
Description of Related Art The present disclosure relates generally to
pharmaceutical compositions and therapeutic approaches involving compounds that have an
anti-cancer effect, particularly through an anti-proliferative mechanism.
2. Description of Related Art
[0003] Telomeres are highly specialized structures which are located at the very end of
linear chromosomes. Normal human somatic cells progressively lose their telomeres with
each cell division primarily due to the end replication problem. While the majority of normal
human cells do not have telomerase activity, 85-90% of cancer cells do, which stabilizes their
telomeres.
[0004] Telomeres are protective structures that are found at the end of linear eukaryotic
chromosomes consisting of multiple copies of TTAGGG DNA repeats. Telomeres are
associated with six proteins; TRF1, TRF2, TIN2, Rap1, TPP1 and POT1, which all together
are called the shelterin complex. (de Lange T., “Shelterin: the protein complex that shapes
and safeguards human telomeres,” Genes & Development 2005;19:2100-10.) The shelterin
complex is present at telomeres throughout the cell cycle and have been shown to cap the
chromosomal ends from being recognized as DNA damage sites.
Telomeres in all normal somatic cells undergo progressive shortening with each
cell division due to the end replication problem, eventually resulting in cellular senescence.
However, replication-dependent telomeric shortening can be counteracted by the
ribonucleoprotein enzyme, telomerase. Telomerase is a cellular reverse transcriptase that
adds TTAGGG repeats to the end of linear chromosomes. Telomerase has two components,
hTERT (telomerase catalytic protein component) and hTR or hTERC (telomerase functional
or template RNA component). (Greider CW and Blackburn EH, “Telomeres, telomerase and
cancer,” Scientific American. 1996;274:92-7.) While most normal somatic human cells do
not have telomerase activity, it is detected, almost universally, in primary human cancer cells
(~85-90%). Thus, the progressive shortening in normal cells without telomerase activity
provide an initial barrier for tumorigenesis.
Therefore, in cancer cells telomerase and telomeres represent attractive almost
universal targets for therapeutic approaches. Because most normal somatic cells do not have
telomerase activity, treatments that selectively target telomerase activity can be beneficial. In
addition, treatments that can interfere with telomere sequencing during telomerase activity to
interfere with the structure or function of the shelterin complex can also be beneficial. It is an
object of the invention to address these benefits, and/ or to at least provide the public with a
useful choice.
SUMMARY
[0006A] In a first aspect, the invention relates to use of 6-thio-deoxyguanosine (6-thio-dG) in
the manufacture of a medicament for treating a telomerase-expressing cell characterized by
an over-activation of telomerase in a subject, wherein the medicament does not include a
telomerase inhibitor.
[0006B] In a second aspect, the invention relates to a method of treating a telomerase-
expressing cell characterized by an over-activation of telomerase in a non-human subject
comprising administering a pharmaceutical composition comprising 6-thio-deoxyguanosine
(6-thio-dG) to the non-human subject, wherein the pharmaceutical composition does not
include a telomerase inhibitor.
BRIEF DESCRIPTION
The present disclosure relates to the use of the compound 6-mercaptopurine
ribonucleoside and analogues thereof for the treatment of tumors, cancer, and
hyperproliferative diseases. Specifically, compounds of the present disclosure can be
convereted into telomere substrates in vivo and can be recognized by telomerase for
incorporation into telomeres of telomerase active cells, leading to induction of cell death of
the telomerase active cells. While not wishing to be bound by any particular theory,
incorporation of the described compounds into the telomere is believed to be an immediate
teloemere DNA chain terminator and/or recognized as having telomeric DNA damage due to
the altered telomere structure.
[0008] In accordance with the present disclosure, a compound according to Formula I
below can be administered to a subject:
where R can be an H, hydroxyl group, an amino group, an alkyl amino group, a fluoride, an
acyl group, a C1-C20 alkyl or ether group, a phosphate, diphosphate, triphosphate,
phosphonate, or a phosphodiester group; where R’ can be an H, a hydroxyl group, flouride
group, a C1-C20 alkyl or ether group; where R” can be a hydroxyl group, a flouride, or an
amino group in the ribo or arabino configuration; where R can be an amino group or a alkyl-
amino group; and pharmaceutically acceptable salts, solvates or polymorphs thereof. In
various embodiments, R. is H, R’ is a hydroxyl group, and R” is H and such compounds are
referred to herein as 6-thio-2’-deoxyguanosine.
In accordance with the present disclosure, a compound according to Formula II
below can be administered to a subject:
where R can be an H, an acyl group, a C -C alkyl or ether group, a phosphate, diphosphate,
1 20
triphosphate, phosphonate, or a phosphodiester group; where R’ can be an H, a hydroxyl
group, flouride, a C -C alkyl or ether group; where R” can be a hydroxyl group, a flouride,
1 20
or an amino group in the ribo or arabino configuration; where R can be an amino group or a
alkyl-amino group; and pharmaceutically acceptable salts, solvates or polymorphs thereof. In
various embodiments, R is H, R’ is a hydroxyl group, and R” is H.
[0010] In accordance with the present disclosure, a pharmaceutical composition can
comprise a compound according to Formula III below can be administered to a subject:
where R can be an H, -C(O)(CH ) CH where n = 6-16 and such compounds are referred to
2 n 3
herein as 6-thio-2’-deoxyguanosine.
[0011] In accordance with the present disclosure, a pharmaceutical composition can
comprise a compound according to Formula IV below can be administered to a subject:
where R can be spermine or spermidine and such compounds are referred to herein as 6-thio-
2’-deoxyguanosine.
In accordance with the present disclosure, a pharmaceutical composition can
comprise a compound according to Formula V below can be administered to a subject:
where R can be spermine or spermidine and such compounds are referred to herein as 6-thio-
2’-deoxyguanosine.
Pharmaceutical compositions comprising an anti-cancer effective amount of one or
more of the compounds of Formula I, II, III, IV, or V, optionally in combination with an
effective amount of at least one additional anti-cancer agent or at least one carrier, additive or
excipient are additional embodiments of the present disclosure.
[0014] Further embodiments of the present disclosure relate to methods for treating cancer
and other hyperproliferative diseases, including tumors, especially malignant tumors and
cancer, and any cell which possesses an over-activation of telomerase.
Other embodiments of the present disclosure comprise a method of treatment
comprising administering an effective amount of 6-mercaptopurine ribonucleoside analogue
according to the present disclosure and administering a second pharmaceutical composition
comprising another anti-cancer agent. Administration can occur simultaneously, in
sequential stages, or be administered stages wherein the stages at least partially overlap in
time or are spaced apart by an certain interval of time. The multiple anti-cancer agent
treatment can provide an additive effect or further a synergistic enhancement of the
anticancer activity of one or both of the anti-cancer agents.
Embodiments discussed in the context of methods or compositions of the
disclosure can be employed with respect to any other method or composition described
herein. Thus, an embodiment pertaining to one method or composition may be applied to
other methods and compositions of the description as well. As used herein the specification,
“a” or “an” may mean one or more. As used herein in the claim(s), when used in conjunction
with the word “comprising”, the words “a” or “an” may mean one or more than one.
The use of the term “or” in the claims is used to mean “and/or” unless explicitly
indicated to refer to alternatives only or the alternatives are mutually exclusive, although the
disclosure supports a definition that refers to only alternatives and “and/or.” As used herein
“another” may mean at least a second or more.
Throughout this application, the term “about” is used to indicate that a value
includes the inherent variation of error for the device, the method being employed to
determine the value, or the variation that exists among the study subjects.
Other objects, features and advantages of the present invention will become
apparent from the following detailed description. It should be understood, however, that the
detailed description and the specific examples, while indicating preferred embodiments of the
invention, are given by way of illustration only, since various changes and modifications
within the spirit and scope of the invention will become apparent to those skilled in the art
from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
The following drawings form part of the present specification and are included to
further demonstrate certain embodiments of the present description. The description may be
better understood by reference to one or more of these drawings in combination with the
detailed description of specific embodiments presented herein.
[0021] The chemical structures of 6-thioguanine (6-thio-G) and 6-thio-
deoxyguanosine (6-thio-dG).
. A graph demonstrating the cell counts of HCT116 and BJ cells treated
with 6-thio-dG (3μM) and 6-thio-G (3μM) for 1 week (every 3 days). (Control; untreated)
Time table of HCT116 cells treatment protocols with no drug (--), 6-thio-
dG (6dG), GRN163L (Im) or combination of 6-thio-dG and GRN163L (combo). Each week
1x10 cells/sample were collected for TRF analysis. HCT116 cells were treated 10μM 6-thio-
dG for 12-16 weeks. After treating with 10μM 6-thio-dG for 12 weeks, the cells were treated
with combination of 10μM 6-thio-dG and 3μM GRN163L for 2-4 weeks or only GRN163L
for 2-4 weeks or cessation of drug for 2-4 weeks. (Control; untreated). TRF analysis was
used to ascertain telomere shortening at the end of each treatment protocol.
FIGS. 3A and 3B. (A) An comparative line graph showing the lag period between
administration of a telomerase inhibitor and cell death for cells with short telomeres and long
telomeres. (B) An comparative line graph showing the lag period between administration of
a telomere-altering compounds and cell death for cells with short telomeres and long
telomeres.
DNA damage foci per cell. HCT116 cells treated with 6-thio-dG (3μM)
and 6-thio-G (3μM) (n=75, SDs from two independent experiments). **P=0.003,
***P=0.0005, *P=0.0141 (6-thio-G versus 6-thio-dG), in the unpaired Student t test. ns, not
significant differences in the unpaired Student t test. (Control; untreated).
TIF index (percentage of TIF positive cells) of HCT116 cells treated with
6-thio-dG (3μM) or 6-thio-G (3μM). Cells with four or more gamma-H2AX foci colocalizing
with TRF2 were scored as TIF positive by Imaris software (n=75, SDs from two independent
experiments). *P<0.05, **P=0.0063 (compared with vehicle control), in the unpaired
Student t test. ns, not significant differences in the unpaired Student t test. (Control;
untreated).
FIGS. 6A and 6B. (A) Line graph showing the survival fraction of HCT116
treated with 6-thio-dg (3μM) and 6-thio-G (3μM), and after 72 hours, were irradiated with
various doses of ionizing radiation. Following the treatment cells were seeded at different
densities and the cultured for 10 days. (B) Line graph showing cell viability determined
using a cell titer glow luminescent assay.
FIGS. 7A and 7B. (A) Line graph showing a reduction in the rate of tumor growth
in Xenograft animal models with HCT116. (B) Line graph showing a reduction in the rate of
tumor growth in Xenograft animal models with A549 cells.
FIGS. 8A and 8B. (A) Line graph showing the weight loss in WT mice models
models receiving 1.67 mg/kg of 6-thio-dG or 6-thio-G, as compared to a control. (B) Line
graph showing the weight loss in WT mice models receiving 5 mg/kg of 6-thio-dG or 6-thio-
G, as compared to a control.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
The present disclosure is directed toward pharmaceutical compositions and
treatment methods using 6-thioguanosine analogues as telomere disrupting compounds.
These analogues can be converted in vivo to 5’-triphosphate telomerase substrates, e.g., 2’-
deoxyguanosine 5’-triphosphate. The described substrates can be incorporated into telomeres
causing telomere shortening, telomere dysfunction, or both.
More specifically, analogues of the present disclosure can act as a telomere
targeting molecule in cancer cells, but generally not (or much less so) in normal telomerase
activity negative cells. This generally selective treatment results from the fact that analogues
of the present disclosure targets cancer cells expressing telomerase. Treatment of telomerase
active cells with the Formula I, II, III, IV, and/or V compound can result in acute cell death in
at least a portion or majority of the active cells. The cell death can be the effect of
progressive telomere shortening or telomere dysfunction, e.g., causing a telomere-associated
DNA damage, since some guanine bases will be replaced by 6-thio-guanine counterparts and
inducing a DNA damage response such as through the alteration of the structure and function
of the shelterin complex. Further, compounds of the present disclosure may not cause any or
may cause only a slight inhibition of telomerase activity in vitro, as tested by Telomeric
Repeat Amplification Protocol (TRAP) assay. Lastly, compounds of the present disclosure
may cause genomic DNA damage. Hence, administration of the various pharmaceutical
compositions in accordance with the present disclosure represent a an approach to treatment
of telomerase positive human cancers based on a bifunctional mechanism of action
characterized as i) acute cytotoxicity derived from anti-metabolic properties and
incorporation into genomic DNA and ii) telomeric DNA modification and shortening. The
present disclosure is also directed to methods of treatment comprising a combination
treatment plan or a coadministration of second pharmaceutical composition.
[0032] In accordance with the present disclosure, a pharmaceutical composition can
comprise the compound 6-mercaptopurine ribonucleoside and analogues thereof for the
treatment of tumors, cancer, and hyperproliferative diseases. In various embodiments, a
pharmaceutical composition can comprise a compound according to Formula I below can be
administered to a subject:
where R can be an H, hydroxyl group, an amino group, an alkyl amino group, a fluoride, an
acyl group, a C -C alkyl or ether group, a phosphate, diphosphate, triphosphate,
1 20
phosphonate, or a phosphodiester group; where R’ can be an H, a hydroxyl group, flouride
group, a C1-C20 alkyl or ether group; where R” can be a hydroxyl group, a flouride, or an
amino group in the ribo or arabino configuration; where R can be an amino group or a alkyl-
amino group; and pharmaceutically acceptable salts, solvates or polymorphs thereof, and
such compounds are referred to herein as 6-thio-2’-deoxyguanosine. In various
embodiments, R. is H, R’ is a hydroxyl group, and R” is H.
In various embodiments, a pharmaceutical composition can comprise a compound
according to Formula II below can be administered to a subject:
where R can be an H, an acyl group, a C -C alkyl or ether group, a phosphate, diphosphate,
1 20
triphosphate, phosphonate, or a phosphodiester group; where R’ can be an H, a hydroxyl
group, flouride, a C -C alkyl or ether group; where R” can be a hydroxyl group, a flouride,
1 20
or an amino group in the ribo or arabino configuration; where R can be an amino group or a
alkyl-amino group; and pharmaceutically acceptable salts, solvates or polymorphs thereof. In
various embodiments, R. is H, R’ is a hydroxyl group, and R” is H and such compounds are
referred to herein as 6-thio-2’-deoxyguanosine.
In various embodiments, a pharmaceutical composition can comprise a compound
according to Formula III below can be administered to a subject:
where R can be an H, -C(O)(CH ) CH where n = 6-16 and pharmaceutically acceptable
2 n 3
salts, solvates or polymorphs thereof, and such compounds are referred to herein as 6-thio-2’-
deoxyguanosine.
In various embodiments, a pharmaceutical composition can comprise a compound
according to Formula IV below can be administered to a subject:
where R can be spermine or spermidine and pharmaceutically acceptable salts, solvates or
polymorphs thereof, and such compounds are referred to herein as 6-thio-2’-deoxyguanosine.
In various embodiments, a pharmaceutical composition can comprise a compound
according to Formula V below can be administered to a subject:
where R can be spermine or spermidine and pharmaceutically acceptable salts, solvates or
polymorphs thereof, and such compounds are referred to herein as 6-thio-2’-deoxyguanosine.
[0036A] The term “comprising” as used in this specification and claims means “consisting at
least in part of”. When interpreting statements in this specification, and claims which include
the term “comprising”, it is to be understood that other features that are additional to the
features prefaced by this term in each statement or claim may also be present. Related terms
such as “comprise” and “comprised” are to be interpreted in similar manner.
The term “alkyl” shall mean within its context a C -C , preferably a C -C linear,
1 20 1 10
branch-chained or cyclic fully saturated hydrocarbon radical, which may be optionally
substituted, such as with a phenyl group, for example. The term alkyl shall also embrace
aralkyl groups such as benzyl groups, which phenyl group may be optionally substituted.
Functional groups not expressly provided are understood to one of a hydrogen or alkyl group
as defined herein. The term “ether” shall mean a C to C ether group, formed from an
1 20
oxygen and an alkyl group at a position on the sugar moiety of compounds according to the
present description, and preferably contains at least one oxygen group within the alkyl chain.
The term “acyl” is used throughout the specification to describe a group at the 5’
position of the nucleoside analog (e.g., at the free hydroxyl position in the sugar unit) which
contains a C1 to C20 linear, branched or cyclic alkyl chain or a related group as otherwise
described herein. The acyl group at the 5’ position (R), in combination with the
corresponding hydroxyl group results in an ester, which, after administration, may be cleaved
to produce the free nucleoside form of the present description.
The term “phosphodiester” describes mono-phosphate groups at the 5’ position of
the sugar unit which are diesterified such that the phosphate group is rendered neutral, i.e.,
has a neutral charge.
Modifications of the Formula I, II, III, IV, or V compounds, particularly at the 5’
position, can affect the solubility, bioavailability and rate of metabolism of the active species,
thus providing control over the delivery of the active species. Further, the modifications can
affect the anticancer activity of the compound, in some cases increasing the activity over the
native guanine compound. This can be assessed by preparing the derivative and testing its
anticancer activity according to the methods described herein, or other method known to
those skilled in the art.
As used herein, “treatment” and “treating” refer to administration or application of
a therapeutic agent to a subject or performance of a procedure or modality on a subject for the
purpose of obtaining a therapeutic benefit with respect to a disease or health-related condition
or a prophylactic effect with respect to a disease or health-related condition. For example, a
treatment may include administration of a pharmaceutically effective amount of a 2-amino
mercaptopurine ribonucleoside analogue to a subject having cancer cells. As used herein, the
term “therapeutic benefit” or “therapeutically effective” refers to a promotion or
enhancement of the well-being of the subject or increases the likelihood thereof with respect
to the medical treatment of a disease or health related condition. This includes, but is not
limited to, a reduction in the frequency or severity of the signs or symptoms of a disease. For
example, treatment of cancer may involve, for example, a reduction in the size of a tumor, a
reduction in the invasiveness of a tumor, reduction in the growth rate of the cancer,
senescence of a portion of cells that exhibit an abnormal activation of telomerase, or
prevention of metastasis or recurrence. Treatment of cancer may also refer to prolonging
survival of a subject with cancer. As used herein, the phrase “effective amount” describes an
amount of a compound which, in context, is used to produce or affect a therapeutic benefit.
As used herein, the phrase “anti-cancer effect” refers to an effect that can include
one or more of inhibiting further growth of tumor or cancer cells; reducing the likelihood or
eliminating metastasis; contributing to cell death in the tumor, cancer cells, or other cells
with an abnormal activation of telomerase; resulting in a shrinkage of the tumor or a
reduction in the number of cancer cells; or preventing the regrowth of a tumor or cancer after
the patient’s tumor or cancer is in remission. Compositions or derivatives thereof in
accordance with the present disclosure exhibit an anti-cancer effect.
[0043] A “subject” refers to either a human or non-human, such as primates, mammals,
and vertebrates. In particular embodiments, the subject is a human.
In accordance with various embodiments, a method of treatment can comprise
administering to a subject a pharmaceutical composition comprising one or more 6-
mercaptopurine ribonucleoside or analogues thereof, e.g., a Formula I, II, III, IV, and/or V
compound. The method can be used in the treatment of a cancer or other hyperproliferative
disease state or in the treatment of cells exhibiting pronounced telomerase activity. The
cancer may be a solid tumor, metastatic cancer, or non-metastatic cancer. In certain
embodiments, the cancer may originate in the bladder, blood, bone, bone marrow, brain,
breast, colon, esophagus, duodenum, small intestine, large intestine, colon, rectum, anus,
gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis,
tongue, or uterus. A tumor can comprise a malignant or benign growth or tumefacent.
The cancer may specifically be of the following histological type, though it is not
limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and
spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma;
lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell
carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant;
cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and
cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma
in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid
tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma;
chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil
carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma;
papillary and follicular adenocarcinoma; non-encapsulating sclerosing carcinoma; adrenal
cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine
adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid
carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous
cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring
cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma;
inflammatory carcinoma; paget’s disease, mammary; acinar cell carcinoma; adenosquamous
carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal
tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma,
malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant;
paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma;
glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading
melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; blue
nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma;
liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar
rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor;
nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner
tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant;
dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant;
choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma,
malignant; kaposi’s sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma;
osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant;
mesenchymal chondrosarcoma; giant cell tumor of bone; ewing’s sarcoma; odontogenic
tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic
fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma;
astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma;
oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma;
ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor;
meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor,
malignant; malignant lymphoma; hodgkin’s disease; hodgkin’s; paragranuloma; malignant
lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant
lymphoma, follicular; mycosis fungoides; other specified non-hodgkin’s lymphomas;
malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small
intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia;
lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic
leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid
sarcoma; and hairy cell leukemia.
Nonetheless, it is also recognized that the present description may also be used to
treat a non-cancerous disease associated with activation of telomerase in inflammatory
(leukocyte) cells (e.g., a fungal infection, a bacterial infection, a viral infection, acute and
chronic inflammatory diseases such as inflammatory bowel disease (Crohn’s disease,
ulcerative colitis), rheumatoid arthritis and/or a neurodegenerative disease associated with
inflammation).
A hyperproliferative disease state comprises a disease state in which cells are
growing in an uncontrolled manner, whether that growth is cancerous or not. Such a disease
state may be reflected in psoriasis, genital warts or other hyperproliferative cell growth
diseases, including hyperproliferative keratinocyte diseases including hyperkeratosis,
ichthyosis, keratoderma or lichen planus, all of which disease states may be treated using
compounds according to the present description. The method embodiment includes treating
hyperproliferative diseases including psoriasis, genital warts and hyperproliferative cell
growth diseases, including hyperproliferative keratinocyte diseases such as hyperkeratosis,
ichthyosis, keratoderma or lichen planus and other chronic inflammatory diseases such as
osteoarthritis hepatitis C virus (HCV) infections, the methods comprising administering to a
patient in need thereof an effective amount of a Formula I, II, III, IV, and/or V compound
according to the present disclosure, optionally in combination with at least one additional
anti-cancer agent, optionally in combination with a pharmaceutically acceptable carrier,
additive or excipient.
Pharmaceutical compositions in accordance with certain embodiments of the
present disclosure can comprise an effective amount of one or more a Formula I, II, III, IV, or
V compound and optionally an additional active ingredient dissolved or dispersed in a
pharmaceutically acceptable carrier.
[0049] As used herein, the term “pharmaceutically acceptable” refers to those compounds,
materials, compositions, and/or dosage forms which are, within the scope of sound medical
judgment, suitable for contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem complications commensurate
with a reasonable benefit/risk ratio. The term “pharmaceutically acceptable carrier,” means a
pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler,
diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a
chemical agent.
The pharmaceutical composition can be administered to a subject by any method
known to those of ordinary skill in the art. Examples may include, but not be limited to
administration intravenously, intradermally, intrathecally, intraarterially, intraperitoneally,
intramuscularly, subcutaneously; orally, intrarectally, mucosally (intranasal, intravaginal,
etc.), topically (i.e., transdermally), locally, via inhalation (e.g., aerosol inhalation), via
injection, via infusion, via continuous infusion, via localized perfusion bathing target cells
directly, via a catheter, via a lavage, in creams, in lipid compositions (e.g., liposomes), or by
other method or any combination of the forgoing as would be known to one of ordinary skill
in the art (see, for example, Remington’s Pharmaceutical Sciences, 18th Ed. Mack Printing
Company, 1990, incorporated herein by reference).
The pharmaceutical composition may be formulated into a composition in a free
base, neutral or salt form. Pharmaceutically acceptable salts, include the acid addition salts,
e.g., those formed with the free amino groups of a proteinaceous composition, or which are
formed with inorganic acids such as for example, hydrochloric or phosphoric acids, or such
organic acids as acetic, oxalic, tartaric or mandelic acid. Salts formed with the free carboxyl
groups can also be derived from inorganic bases such as for example, sodium, potassium,
ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine,
trimethylamine, histidine or procaine. Upon formulation, solutions will be administered in a
manner compatible with the dosage formulation and in such amount as is therapeutically
effective.
In embodiments where the composition is in a liquid form, a carrier can be a
solvent or dispersion medium comprising but not limited to, water, ethanol, polyol (e.g.,
glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipids (e.g., triglycerides,
vegetable oils, liposomes) and combinations thereof. The proper fluidity can be maintained,
for example, by the use of a coating, such as lecithin; by the maintenance of the required
particle size by dispersion in carriers such as, for example liquid polyol or lipids; by the use
of surfactants such as, for example hydroxypropylcellulose; or combinations thereof such
methods. It may be preferable to include isotonic agents, such as, for example, sugars,
sodium chloride or combinations thereof.
[0053] The actual dosage amount of a composition in accordance with certain
embodiments of the present disclosure administered to subject can be determined by physical
and physiological factors such as the specific compound employed, the age, general health of
the subject, diet, body weight, severity of condition, the type of disease being treated,
previous or concurrent therapeutic interventions, idiopathy of the patient, absorption rates,
distribution rates, inactivation rates, excretion rates, , time of administration, the route of
administration, and on the , judgment of the person supervising the administration.
Depending upon the dosage and the route of administration, the number of administrations of
a preferred dosage, and/or an effective amount may vary according to the response of the
subject. The active ingredient may be administered at once, or may be divided into a number
of smaller doses to be administered at varying intervals of time. As such, it is understood that
for any particular subject, specific dosage regimens could be adjusted over time according to
the individual need and the professional judgment of the person administering or supervising
the administration of the compositions, and that the concentration ranges set forth herein are
exemplary only and are not intended to limit the scope or practice of the claimed
composition.
The Formula I, II, III, IV, and/or V compound is included in the pharmaceutically
acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically
effective amount for the desired indication, without causing serious toxic effects in the patient
treated. A preferred dose of the active compound for all of the herein-mentioned conditions is
in the range from about 10 ng/kg to 100 mg/kg, preferably 0.1 to 50 mg/kg per day, more
generally 0.5 to about 25 mg per kilogram body weight of the subject per day. By way of
non-limiting example, a typical dosage can range from 0.01-20% wt/wt in a suitable carrier.
Similarly, the compound can be administered in any suitable unit dosage form, including but
not limited to one containing less than 1 mg, 1 mg to 3000 mg, or 5 to 1000 mg of active
ingredient per unit dosage form.
Compositions may be administered on an ongoing or continuous basis; on an as
needed basis; or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more
times. They may be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24 hours, or 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, 5 weeks, or 1, 2, 3, 4,
, 6, 7, 8, 9, 10, 11, 12 months or more. (or any value derivable therein). Similarly, it is
specifically contemplated that the composition may be administered once daily, twice daily,
three times daily, four times daily, five times daily, or six times daily (or any range derivable
therein) and/or as needed to the patient. A dose may be first administered before or after
detection of a disease or health related condition or subsequent to a test where no disease
indicators are detected. In some embodiments, the patient can be administered a composition
in cycles of days or weeks and in between each cycle, no drug is administered between
cycles. The time between each cycle can be days or weeks, e.g., 2-8 days/weeks. In some
embodiments, the patient is administered the composition for a certain period of time or with
a certain number of doses after there is no detectable presence of a disease or disorder.
Similarly, in various embodiments, the composition may be administered to (or
taken by) the patient about, at least about, or at most about 0.01-1000 μl/min, μl/hour, μl/day,
μl/week, μl/month, ml/min, ml/hour, ml/day, ml/week, ml/month, μg/min, μg/hour, μg/day,
μg/week, μg/month, mg/min, mg/hour, mg/day, mg/week, mg/month or any range derivable
therein.
In order to increase the effectiveness a treatment, it may be desirable to combine
compositions of the present disclosure with a second treatment or pharmaceutical
composition. For example, a method of use can further include administration of a second
pharmaceutical composition comprising an anti-cancer agent or other agent effective in the
treatment of hyperproliferative disease. An anti-cancer agent can negatively affect cancer in
a subject, for example, by killing cancer cells, inducing apoptosis in cancer cells, reducing the
growth rate of cancer cells, reducing the incidence or number of metastases, reducing tumor
size, inhibiting tumor growth, reducing the blood supply to a tumor or cancer cells,
promoting an immune response against cancer cells or a tumor, preventing or inhibiting the
progression of cancer, or increasing the lifespan of a subject with cancer. More generally, a
second pharmaceutical composition can be administered in an effective amount or combined
effective amount to kill or inhibit proliferation of certain cells.
In various embodiments, a method of treatment can comprise a simultaneous co-
administration. This process may involve administration at the same time. This can be
achieved by contacting the cell with a single composition or pharmaceutical formulation that
includes both a Formula I, II, III, IV, and/or V compound and another anti-cancer agent, or
by contacting the cell with two distinct compositions or formulations, at the same time,
wherein one composition includes the Formula I, II, III, IV, and/or V compound and the other
includes the second agent(s). Similarly, two compositions can be administered not at the
same time but in temporal proximity to each other, e.g., on the same day or within the same
week.
In various embodiments a method of treatment can comprise a first stage wherein a
pharmaceutical composition comprising a Formula I, II, III, IV, and/or V compound is
administered and a second stage where a second pharmaceutical composition is administered.
The first stage and the second stage may be sequential in time, spaced apart in time (minutes,
days, weeks, or months), or overlapping in time. In addition, the sequential order of
treatment stages can be reversed or repeated.
To be sure, any combination of treatment stages may be employed. By way of
example, administration of a Formula I, II, III, IV, and/or V compound is “A” and the
treatment with a secondary agent is “B”:
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A
B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
In the context of the present disclosure, it is contemplated that administration of a
pharmaceutical composition comprising a Formula I, II, III, IV, and/or V compound could be
used in conjunction with a treatment B, such as gene therapy, chemotherapeutic,
radiotherapeutic, or immunotherapeutic intervention, in addition to other pro-apoptotic or cell
cycle regulating agents. It also is contemplated that various standard therapies, as well as
surgical intervention, may be applied in combination with the described telomere shortening
and telomere dysfunction-inducing therapy.
a. Chemotherapy
Chemotherapies include, for example, cisplatin (CDDP), carboplatin, procarbazine,
mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil,
busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin,
mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol,
gemcitabien, navelbine, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil,
vincristin, vinblastin and methotrexate, or any analog or derivative variant of the foregoing.
b. Radiotherapy
Radiotherapies can cause DNA damage and include what are commonly known as
-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells. Other forms of
DNA damaging factors are also contemplated such as microwaves and UV-irradiation.
c. Immunotherapy
Immunotherapeutics, generally, rely on the use of immune effector cells and
molecules to target and destroy cancer cells. Immunotherapy, thus, could be used as part of a
combined therapy, in conjunction with the administration of a pharmaceutical composition
comprising a Formula I, II, III, IV, and/or V compound. Immunotherapy modality relates to
the targeting of the tumor cell through some marker of the tumor cell that is amenable to
targeting, i.e., is not present on the majority of other cells. Many tumor markers exist and
any of these may be suitable for targeting with a second treatment modality in the context of
the present disclosure. Common tumor markers include carcinoembryonic antigen, prostate
specific antigen, urinary tumor associated antigen, fetal antigen, tyrosinase (p97), gp68,
TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor, laminin
receptor, erb B and p155.
d. Genes
In yet another embodiment, the secondary treatment B is a gene therapy in which a
therapeutic polynucleotide encoding all of part of a polypeptide is administered before, after,
or at the same time as a pharmaceutical composition comprising a Formula I, II, III, IV,
and/or V compound. Delivery of vector encoding a certain gene product(s) related to the
particular disease or health related condition can have a combined therapeutic effect, e.g.,
anti-proliferative effect, on target tissues.
e. Surgery
[0066] Curative surgery is a cancer treatment that can be used in conjunction with a
pharmaceutical composition comprising a Formula I, II, III, IV, and/or V compound.
Curative surgery includes resection in which all or part of cancerous tissue is physically
removed, excised, and/or destroyed. Tumor resection refers to physical removal of at least
part of a tumor. In addition to tumor resection, treatment by surgery includes laser surgery,
cryosurgery, electrosurgery, and miscopically controlled surgery (Mohs’ surgery). It is
further contemplated that composition of the present disclosure can be administered in
conjunction with removal of superficial cancers, precancers, or incidental amounts of normal
tissue. Upon excision of part of all of cancerous cells, tissue, or tumor, a cavity may be
formed in the body. Treatment may be accomplished by administration of a pharmaceutical
composition comprising a Formula I, II, III, IV, and/or V compound.
f. Other anti-cancer agents
It is contemplated that other anti-cancer agents may be used in combination with
Formula I, II, III, IV, and/or V compositions of the present disclosure to additively or
synergistically enhance the therapeutic efficacy of treatment.
These additional agents include immunomodulatory agents, agents that affect the
upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation
agents, inhibitors of cell adhesion, or agents that increase the sensitivity of the
hyperproliferative cells to apoptotic inducers. Immunomodulatory agents include tumor
necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other
cytokine analogs; or MIP-1, MIP-1beta, MCP-1, RANTES, and other chemokines. It is
further contemplated that the up-regulation of cell surface receptors or their ligands such as
Fas / Fas ligand, DR4 or DR5 / TRAIL would potentiate the apoptotic inducing abilities of
the present disclosure by establishment of an autocrine or paracrine effect on
hyperproliferative cells. Increases intercellular signaling by elevating the number of GAP
junctions would increase the anti-hyperproliferative effects on the neighboring
hyperproliferative cell population. In other embodiments, cytostatic or differentiation agents
can be used in combination with the present description to improve the anti-
hyperproliferative efficacy of the treatments. Inhibitors of cell adhesion are contemplated to
improve the efficacy of the present description. Examples of cell adhesion inhibitors are
focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further contemplated that other
anti-cancer agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such
as telomerase inhibitors like imetelstat sodium and signal transduction inhibitors like the
antibody c225, could be used in combination with the present description to improve the
treatment efficacy. As shown in the Example section, a clinically relevant combination of 6-
thio-deoxyguanosine and imetelstat sodium showed additive effects on telomere shortening in
HCT116 cells. In various embodiments, a method of treatment can comprise administration
of telomere targeting/modifying composition such as a Formula I, II, III, IV, and/or V
compound and a telomerase inhibiting composition such as imetelstat sodium, whether
simultaneously, sequentially or both. Such embodiments can have an additive effect on
telomere shortening.
[0069] Lastly, additional agents can also include anti-cancer agents which are broadly
characterized as anti-metabolites, inhibitors of topoisomerase I and II, alkylating agents and
microtubule inhibitors (e.g., taxol). Anti-cancer agents for use in the present invention
include, for example, Aldesleukin; Alemtuzumab; alitretinoin; allopurinol; altretamine;
amifostine; anastrozole; arsenic trioxide; Asparaginase; BCG Live; bexarotene capsules;
bexarotene gel; bleomycin; busulfan intravenous; busulfan oral; calusterone; capecitabine;
carboplatin; carmustine; carmustine with Polifeprosan 20 Implant; celecoxib; chlorambucil;
cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine;
dactinomycin; actinomycin D; Darbepoetin alfa; daunorubicin liposomal; daunorubicin,
daunomycin; Denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin
liposomal; Dromostanolone propionate; Elliott’s B Solution; epirubicin; Epoetin alfa
estramustine; etoposide phosphate; etoposide (VP-16); exemestane; Filgrastim; floxuridine
(intraarterial); fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin;
goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib
mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole;
lomustine (CCNU); mechlorethamine (nitrogen mustard); megestrol acetate; melphalan (L-
PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane;
mitoxantrone; nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin; oxaliplatin;
paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman;
plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase;
Rituximab; Sargramostim; streptozocin; talbuvidine (LDT); talc; tamoxifen; temozolomide;
teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene;
Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine
(monoval LDC); vinblastine; vinorelbine; zoledronate; and mixtures thereof, among others.
Hormonal therapy may also be used in combination with the administration of a
pharmaceutical composition comprising a Formula I, II, III, IV, and/or V compound. The use
of hormones may be employed in the treatment of certain cancers such as breast, prostate,
ovarian, or cervical cancer to lower the level or block the effects of certain hormones such as
testosterone or estrogen. This treatment is often used in combination with at least one other
cancer therapy as a treatment option or to reduce the risk of metastases.
Preparation and Administration of the Active Compounds and Compositions
Formula I, II, III, IV, or V can be prepared according to the methods disclosed in detail in the
art or by any other method known to those skilled in the art. In the case of compounds which
contain two active agents, linking of a Formula I, II, III, IV, and/or V compound to another
active agent may be readily accomplished following standard techniques. Appropriate
blocking groups and agents to form the linking groups may be used readily.
The following examples are included to demonstrate preferred embodiments of the
invention. It should be appreciated by those of skill in the art that the techniques disclosed in
the examples which follow represent techniques discovered by the inventor to function well
in the practice of the invention, and thus can be considered to constitute preferred modes for
its practice. However, those of skill in the art should, in light of the present disclosure,
appreciate that many changes can be made in the specific embodiments which are disclosed
and still obtain a like or similar result without departing from the spirit and scope of the
invention.
EXAMPLES
Materials and Methods:
Cell lines
[0073] HCT116 represents a human colon cancer cells, A549 models human lung
epithelial cancer cells, H2882 models human lung epithelial cancer cells, HCC2429 models
human lung epithelial cancer cells, HCC827 models human lung epithelial cancer cells,
HCC15 models human lung epithelial cancer cells, H2087 models human lung epithelial
cancer cells, HCC4017 models human lung epithelial cancer cells, HCC515 models human
lung epithelial cancer cells, H2009 models human lung epithelial cancer cells, BJ-hTERT
cells model telomerase expressing normal human fibroblast cells, and BJ human fibroblasts
(telomerase silent) were grown in a Media X (Hyclone, Logan, UT) supplemented with 10%
cosmic calf serum (Hyclone).
Drug preparation
6-thio-dG (Metkinen Oy, Kuopio, Finland) was dissolved in DMSO/water (1:2), 6-
thio-G (Sigma, St Louis, MO) was dissolved in serum free medium, and GRN163L (Geron
Corporation, Menlo Park, CA) was dissolved in phosphate buffer saline (PBS) to prepare 50
mM or 10 mM stock solutions, which were frozen at - 80˚C. After stock solutions were
prepared, they were aliquoted into 1 mM solutions, which were further diluted as needed for
in vitro treatment experiments.
GRN163L (Imetelstat sodium) is a 13-mer thio-phosphoramidate oligonucleotide
with the following sequence: 5′-TAGGGTTAGACAA-3′. Imetelstat has a palmitoyl group at
the 5’-end, that helps the oligonucleotide to pass through cell membranes. The compound is
complementary to the template region of human telomerase RNA subunit (hTR), and it is a
highly potent direct and competitive inhibitor of telomerase. Tumor cell line treatment with
imetelstat results in telomerase inhibition and progressive telomere shortening, leading to cell
senescence or apoptosis in vitro.
Long-term cell culture studies
For long-term cellular experiments, HCT116 (1,000 cells/cm ) and BJ (10,000
cells/cm ) cells were fed with 6-thio-dG (1, 3, 10μM) containing medium every three days.
The cells were counted and replated every week for 10-16 weeks. Additionally, HCT116
cells (1,000 cells/cm ) were fed with 6-thio-G (1, 3, 10μM) every three days and each week
cells were counted, collected for TRF (Telomere Restriction Fragment) analysis and replated.
HCT116 cells, following treatment with 10μM 6-thio-dG for 12 weeks, were then treated
with a combination of 10μM 6-thio-dG and 3μM GRN163L for 2-4 weeks.
Telomerase activity assay
Telomerase activity was measured by the TRAP assay (Telomeric Repeat
Amplification Protocol as described in Shay J.W. and Bacchetti S., “A survey of telomerase
activity in human cancer,” European Journal of Cancer 1997; 33:787-91.). Briefly, HCT116
cells were treated with 1 or 10μM 6-thio-dG for 1-12 weeks. 1x10 cells were collected and
lysed with ice-cold NP-40 lysis buffer (10 mM Tris– HCl pH 8.0, 1.0 mM MgCl2, 1 mM
EDTA, 1% NP-40, 0.25 mM sodium deoxycholate, 10% glycerol, 150 mM NaCl, 5 mM β-
mercaptoethanol) for 30 min. One microliter cellular lysate for 2500 cells was used for each
reaction. Hela cells were used as a positive control and lysis buffer was used as a negative
control. Samples were prepared and then the telomerase extension products were amplified
using PCR (95˚C for 5 min to inactivate telomerase, then 95˚C for 30 sec, 52˚C for 30 sec,
72˚C for 30 sec; 24 cycles). Samples were run on a 10% non-denaturating acrylamide gel and
visualized using a Typhoon PhosphorImager scanner system (Molecular Dynamics, GE
Healthcare, Piscataway, NJ) that is capable of reading Cy5 fluorescence.
Telomere length assay (TRF, Terminal Restriction Fragment)
1x10 cells were collected and washed with PBS. DNA was isolated using the
manufacturer’s instructions (Qiagen, Valencia, CA). 2.5 μg DNA was digested with six
different restriction enzymes (HhaI, HinfI, MspI, HaeIII, RsaI, AluI) (New England Bio,
Ipswich, MA) and incubated at 37 C overnight. Digested DNA was separated on a 0.7%
agarose gel overnight at 70 V. The terminal restriction fragment (TRF) gel was denatured for
min in denaturating solution (0.5 M NaOH, 1.5 M NaCl, pH 13.2) and dried on Whatman
3MM paper under vacuum for 3 hours at 56 C. The gel was neutralized for 15 minutes in
neutralization buffer (1.5 M NaCl, 0.5 M Tris-HCl, pH 8.0) and then probed with a
radiolabeled telomeric probe (C-rich) for 16 hours at 42 C in 5xSSC buffer, 5xDenhardt’s
solution, 10 mmol/L Na HPO , and 1 mmol/L Na H P 0 . The gel was washed once with
2 4 2 2 2 7
2XSSC, 0.1%SDS, twice with 0.5XSSC, 0.1%SDS and then twice with 0.5XSSC, 1%SDS at
room temperature for 15 min. Gels were exposed to a PhosphorImager screen overnight and
analyzed using a Typhoon PhosphorImager scanner system (Molecular Dynamics).
Telomere dysfunction induced foci (TIF) assay
The TIF assay is based on the co-localization detection of DNA damage by an
antibody against DNA damage markers such as gamma-H2AX and telomeres by the
telomeric protein TRF2. Briefly, HCT116 cells were plated in 4-well chamber slides and
after the cells attached to the surface, either 3μM 6-thio-dG or 3μM 6-thio-G was added to
the medium at different time points (0, 30 min, 12 h, 24 h, 48 h, 72 h). Slides were rinsed
once with PBS and fixed in 4% paraformaldehyde in PBS for 10 min. Then, cells were
washed twice with PBS and permeabilized in 0.5% Nonidet-P40 in PBS, blocked with 0.5%
Bovine Serum Albumin (BSA) and 0.2% fish gelatin in PBS for 30 min. gamma-H AX
(mouse) (Millipore, Billerica, MA) was diluted 1:1000 and TRF2 (rabbit) (Abcam,
Cambridge, MA) was diluted 1:200 in blocking solution and this primary Ab mixture was
incubated on cells for 2 h. After three washes with PBST (1x PBS in 0.1% Triton) and 3
washes with PBS, cells were incubated with Alexaflour 488 conjugated goat anti rabbit
(1:500) (Invitrogen, Grand Island, NY) and Alexaflour 568 conjugated goat anti mouse
(1:500) (Invitrogen) for 40 min, then washed six times with PBS. After drying, the slides
were mounted with Vectashield mounting medium with DAPI (Vector Laboratories,
Burlingame, CA). Images were captured with Deltavision wide-field microscope, then
deconvoluted using Autoquant X3. TIFs were quantified using Imaris software.
Statistical analysis
Comparisons of different groups for statistical significance were analyzed using a
two-tailed, unpaired. Student t test. P value of 0.05 or less was considered significant.
Results
Effects of 6-thio-dG and 6-thio-G on cellular morphology
[0081] Cancer HCT116 and normal BJ fibroblast cells were treated with 6-thio-dG (3μM)
and 6-thio-G (3μM) twice during one week. Following one week of the treatment, cell
morphology was monitored, and then the cells were collected and counted. shows
the results of the cell count. Treatment with 6-thio-dG resulted in death of the vast majority
of HCT116 cells. and also changed their morphology, whereas the morphology and cell
counts of normal BJ fibroblasts were only slightly affected.
6-thio-dG, but not 6-thio-G, resulted in progressive telomere shortening in cancer cells
To determine if 6-thio-dG and 6-thio-G causes progressive telomere shortening,
telomere lengths of treated cells were evaluated by TRF assay. Cancer HCT116 and normal
BJ fibroblast cells were treated with 1μM or 10μM of 6-thio-dG for 1-12 weeks every 3 days.
In addition, HCT116 cells were also treated with 1μM or 10μM 6-thio-G for 1-10 weeks
every 3 days to determine if there is any effect of this molecule on telomeric length
maintenance. The control was untreated. Each week samples were collected for TRF
analysis at 1x10 cells/sample at 1, 5, and 12 weeks for cells treated with 6-thio-dG and 1, 5,
and 10 for cells treated with 6-thio-G.
[0083] The results of the TRF assays showed that telomere shortening was detectable as
early as one week and five weeks, with more dramatic telomeres shortening after 12 weeks of
continuous 6-thio-dG treatment. At 12 weeks, both the 1μM or 10μM showed dramatic
telomere shortening. At the same time, treatment with 6-thio-G did not result in any
significant effects on telomere length of HCT116 cells after 10 weeks. This suggested that
intracellular metabolic pathways of 6-thio-dG and 6-thio-G are different, and that 6-thio-dG
is much more readily converted into the corresponding 5’-triphosphate, which is eventually
being recognized by telomerase and incorporated into telomeres.
In addition, BJ fibroblast cells treated with 6-thio-dG or 6-thio-G (data not shown)
for 10 weeks did not show enhanced telomere shortening, as compared to untreated control
cells. When telomerase activity of HCT116 cells treated with 6-thio-dG or 6-thio-G was
evaluated by TRAP assay, no inhibition of telomerase activity was observed for either. (For
the TRAP assay, cells were treated with 1 and 10μM 6-thio-dG every 3 days for 12 weeks.
Each week samples were collected for TRAP analysis at 1x10 cells /sample. The control was
an untreated sample.) This suggests that 6-thio-dG causes telomeric shortening independent
from telomerase inhibition.
6-thio-dG and GRN163L show additive effects on telomere shortening
HCT116 cells were treated with either 10μM 6-thio-dG alone for 12-16 weeks, or
with 3μM GRN163L alone for 11 weeks. Then, these long term 6-thio-dG treated surviving
cells were cultured with a combination of 6-thio-dG (10μM) and/or GRN163L (3μM) for 2-4
additional weeks. shows a table summarizing the types of treatment protocols tested.
Treatment with GRN163L did not show any significant telomere shortening after 11 weeks as
compared to the control. Yet, combination therapy produced additive, if not synergistic,
effects on HCT116 cell telomere shortening. Specifically, the HCT116 cells were treated
beyond the 12 weeks of 6-thio-dG treatment with either GRN163L only or GRN163L + 6-
thio-dG, for an additional 2 and 4 weeks to determine if there is an effect on telomere length.
These cells cultured with 6-thio-dG beyond 12 weeks of treatment with GRN163L, whether
alone or in combination, resulted in increased telomere shortening in HCT116 cells as
compared with cells cultured with 6-thio-dG for 12, weeks, 14 weeks, and 16 weeks. These
results suggest that combination therapy of 6-thio-dG and GRN163L may be more effective
than the single agent therapy with either GRN163L or 6-thio-dG.
Treatment of telomerase positive cancer cells only with 6-thio-dG or only with
GRN163L did exhibit telomere shortening, as compared with the telomerase negative control
cells. However, HCT116 cells treated with 6-thio-dG for 12 weeks and then continued to be
treated with 6-thio-dG exhibited stablized telomeres. In other words, the detected telomere
lengths were approximately the same at 12 weeks and 16 weeks. In addition, when cells
cultured with 6-thio-dG for 12 weeks were then returned to normal medium without drug for
2-4 weeks, the telomere remained about the same as after 12 week of 6-thio-dG treatment.
This suggests that 6-thio-dG treatment does not allow cells to reverse its effects on telomeric
lengths for at least 2 to 4 weeks.
Notably, telomerase inhibitors do not immediately cause cell death. By binding to
telomerase and inhibiting its enzymatic activity telomerase cannot maintain telomere
homeostasis. Indeed, it can take several months to drive the already short telomeres in cancer
cells to become so short that they initiate cell death (apoptosis). Thus, with classic telomerase
inhibitors there is a substantial lag phase before cancer cells die. As demonstrated by the
present study of GRN163L, there was a delay in telomere shortening for GRN163L as
compared to 6-thio-dG. ( (telomerase inhibition) and (telomere altering
(such as uncapping) in telomerase positive cells) show a comparison of this respective lag
times in causing cell death.) The 6-thio-dG shortened this lag period considerably since the
mechanism of causing apoptosis is to have 6-thio-dG be converted to 6-thio-dGTP in the
cells. Such converted compounds are a good and specific substrate for telomerase and can be
incorporated into the telomeres. Thus, compounds of the present disclosure do not inhibit
telomerase but are an immediate telomere chain terminator (that is dependent on the presence
of telomerase) that will be recognized as damaged DNA and will result in rapid initiation of
apoptosis.
6-thio-dG, but not 6-thio-G, resulted in telomere dysfunction induced foci (TIFs) in
telomerase expressing cells
Normal BJ cells and telomere expressing BJ-hTERT cells were seeded in chamber
slides. Following cell attachment, 6-thio-dG (10μM) and 6-thio-G (10μM) were added to
fresh medium of each cell type. To test if 6-thio-dG and 6-thio-G cause telomere dysfunction
in normal cells as compared to telomere expressing cells, TIF analysis was conducted. A
control was used for each cell type as well, where DMSO was added to fresh medium of each
cell type. Using combination of gamma-H2AX and TRF2 immuno-staining we were able to
distinguish between genomic DNA damage and telomere specific damage after 48 hours.
The results are shown in Table 1. As shown, the 6-thio-dG induced telomere induced foci in
BJ-hTERT cells and exhibited more specificity for telomerase expressing cells over normal
cells. In comparison, 6-thio-G did not induce telomere induced foci. This demonstrates that
only telomerase expressing cells will be affected by 6-thio-dG. These include almost all
human cancer cells and certain human diseases involving acute and chronic inflammation.
Table 1:
>4 TIFs per nucleus
Cell types / Drug treatment Number of nuclei scored
background subtracted
BJ-hTERT / DMSO control 104 0
BJ-hTERT / 6-thio-G 94 0
BJ-hTERT / 6-thio-dG 97 14
BJ / DMSO control 102 0
BJ / 6-thio-G 101 0
BJ / 6-thio-dG 100 2
6-thio-dG treatment results in telomere dysfunction in cancer cells
Cancer HCT116 cells were seeded in chamber slides. Following cell attachment,
6-thio-dG (3μM) and 6-thio-G (3μM) were added to fresh medium at various time points (0,
min, 2 h, 12 h, 24 h, 48 h, 72 h). To test if 6-thio-dG and 6-thio-G cause telomere
dysfunction in cancer cells, TIF analysis was conducted. Using combination of gamma-
H2AX and TRF2 immuno-staining we were able to distinguish between genomic DNA
damage and telomere specific damage. 6-thio-dG treatment causes a 2.8-fold increase in
telomeric DNA damage as compared to 6-thio-G after 72 h (Fig. 4). In addition to the
increase in telomere damage by 6-thio-dG, there was also an overall increase in genomic
DNA damage compared to 6-thio-G (Fig. 5). Co-localization of gamma-H2AX and TRF2
show the existence of dysfunctional telomeres, which can leave chromosome ends uncapped
and can induce DNA damage responses, such as cell cycle arrest, senescence, apoptosis and
chromosome end fusions.
6-thio-dg treatment decreases the survival and viability of HCT116 cells
As shown in Fig. 6A, the survival fraction of HCT116 cells treated with 6-thio-dG
is lower than cells treated with 6-thio-G. HCT116 cells were treated with 6-thio-dg (3μM)
and 6-thio-G (3μM), and after 72 hours, were irradiated with various doses of ionizing
radiation. Following the treatment cells were seeded at different densities and the cultured
for 10 days. As shown in Fig. 6B, cell viability of HCT116 cells treated with 6-thio-dG is
lower than cells treated with 6-thio-G. Cell viability was determined using a cell titer glow
luminescent assay.
GI 50 values in a normal cell line and a panel of cancel cell lines demonstrate that 6-thio-dG
was more effective at lower dosages against a variety of cancer cell lines than 6-thio-G
[0092] Cells of each type listed in Table 2 were seeded in chamber slides. GI 50 values
were determined for a panel cancer cell lines and a normal BJ cell line for both 6-thio-dG and
6-thio-G. As shown in Table 2, the GI 50 values were slightly higher for 6-thio-G as
compared with 6-thio-dG in all the cancer cell lines except the H2087, where it was equal.
Thus, 6-thio-dG was more effective at a lower dosage against a variety of cancer cell lines
compared to 6-thio-G. This suggests that 6-thio-dG is a more effective chemotherapeutic
agents compared to an already approved compound, 6-thio-G due to an additional mode of
action. In xenograft and mouse toxicity studies described in the next section, 6-thio-dG is not
only more effective in reducing tumor burden but with less toxicity (e.g. less weight loss).
Table 2:
Cell Type 6-thio-dG (GI 50, μM) 6-thio-G (GI 50, μM)
BJ ˃100 ˃100
HCT116 1.0 1.2
A549 2.1 2.3
H2882 0.4 0.6
HCC2429 0.6 0.7
HCC827 0.8 1.7
HCC15 0.8 1.1
H2087 0.9 0.9
HCC4017 0.9 2.0
HCC515 2.4 4.9
H2009 2.6 3.3
6-thio-dg treatment decreases the rate of tumor growth in xenograft animal models with
HCT116 and A549 cells.
Doses of 2 mg/kg of 6-thio-dG and 2 mg/kg of 6-thio-G were IP injected every two
days for a total of 6 injections into mice. DMSO injections were used for the control. The
volume of the tumor was measured. Fig. 7A shows that the rate of tumor growth was less for
the animal models with HCT116 cells receiving the 6-thio-dG injections.
Doses of 2.5 mg/kg of 6-thio-dG and 2.5 mg/kg of 6-thio-G were injected every
day into mice after tumor implantation and providing time for tumor initiation. DMSO
injections were used for the control. The volume of the tumor was measured. Fig. 7B shows
that the rate of tumor growth was less for the animal models with A549 human lung cancer
cells receiving the 6-thio-dG injections compared to the control and 6-thio-G treated mice. In
addition, upon a histology comparison of the residual tumors, the residual 6-thio-dG tumors
were mostly fibrotic and often associated with apoptotic and inflammatory cells, whereas the
residual 6-thio-G and control tumors exhibited mostly “healthy” growing cancerous cells.
Toxicity testing in rats
[0096] Six rats were treated with 15mg of 6-thio-dG /kg of body weight every two days.
One rat died after 6 injections, the remaining five mice showed no signs of impaired function.
Another 5 rats were treated with 50mg of 6-thio-dG /kg of body weight every other day. All
rats died after 12 days.
Toxicity-weight loss testing in WT mice
[0097] Six WT mice were treated with 1.67 mg of 6-thio-dG /kg of body weight daily.
Six WT mice were treated with 1.67 mg of 6-thio-G /kg of body weight daily. Six WT mice
were treated with 5 mg of 6-thio-dG /kg of body weight daily. Six WT mice were treated
with 5 mg of 6-thio-G /kg of body weight daily. The mice were given the appropriate dosage
and weighed daily for 25 days. The results are shown in FIGS. 8A and 8B. For the mice
administered the lower 1.67 mg/kg dose, an example of an effective cancer dose, no weight
loss was observed for those treated with 6-thio-dG. In comparison, the mice receiving 6-thio-
G at the same dose lost between 1-2 grams (6-12% of initial weight) over the course of the 25
day treatment. For the mice administered the higher 5 mg/kg dose (a 2-3 fold increase over
an effective cancer dose), only modest weight loss was observed for those treated with 6-
thio-dG. In comparison, the mice receiving 6-thio-G at the same dose loss around 2 grams
and all mice died by the 15 day of treatment. Importantly, these results in normal mice
suggest that expected toxicities associated with treating cancer patients 6-thio-dG are
expected to be significantly less compared to the already approved 6-thio-G compound. In
addition, there is a significant tumor reduction effect of 6-thio-dG at ~3-fold lower doses that
do not cause weight loss in mice.
All of the compositions and methods disclosed and claimed herein can be made
and executed without undue experimentation in light of the present disclosure. While the
compositions and methods of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that variations may be applied to
the compositions and methods and in the steps or in the sequence of steps of the method
described herein without departing from the concept, spirit and scope of the invention. More
specifically, it will be apparent that certain agents which are both chemically and
physiologically related may be substituted for the agents described herein while the same or
similar results would be achieved. All such similar substitutes and modifications apparent to
those skilled in the art are deemed to be within the spirit, scope and concept of the invention
as defined by the appended claims.
[0098A] Certain statements that appear herein are broader than what appears in the
statements of the invention. These statements are provided in the interests of providing the
reader with a better understanding of the invention and its practice. The reader is directed to
the accompanying claim set which defines the scope of the invention.
[0098B] In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that
such documents, or such sources of information, in any jurisdiction, are prior art, or form part
of the common general knowledge in the art.
The following numbered paragraphs define particular embodiments of the present
description:
1. A pharmaceutical composition comprising a 6-mercaptopurine ribonucleoside
analogue, for use in treating cancer or a hyperproliferative disease.
2. The composition of paragraph 1, wherein the 6-mercaptopurine ribonucleoside
analogue comprises 6-thio-2’-deoxyguanosine.
3. The composition of paragraph 1, wherein the 6-mercaptopurine ribonucleoside
analogue is a compound according to the following formula:
where R can be an H, hydroxyl group, an amino group, an alkyl amino group, a fluoride, an
acyl group, a C -C alkyl or ether group, a phosphate, diphosphate, triphosphate,
1 20
phosphonate, or a phosphodiester group; where R’ can be an H, a hydroxyl group, flouride
group, a C -C alkyl or ether group; where R” can be a hydroxyl group, a flouride, or an
1 20
amino group in the ribo or arabino configuration; where R can be an amino group or a alkyl-
amino group; and pharmaceutically acceptable salts, solvates or polymorphs thereof.
4. The composition of paragraph 1, wherein the 6-mercaptopurine ribonucleoside
analogue is a compound according to the following formula:
where R can be an H, an acyl group, a C -C alkyl or ether group, a phosphate, diphosphate,
1 20
triphosphate, phosphonate, or a phosphodiester group; where R’ can be an H, a hydroxyl
group, flouride, a C -C alkyl or ether group; where R” can be a hydroxyl group, a flouride,
1 20
or an amino group in the ribo or arabino configuration; where R can be an amino group or a
alkyl-amino group; and pharmaceutically acceptable salts, solvates or polymorphs thereof.
. The composition of paragraph 1, wherein the 6-mercaptopurine ribonucleoside
analogue is a compound according to the following formula:
where R can be an H, -C(O)(CH ) CH where n = 6-16 and pharmaceutically acceptable
2 n 3
salts, solvates or polymorphs thereof.
6. The composition of paragraph 1, wherein the 6-mercaptopurine ribonucleoside
analogue is a compound according to the following formula:
where R can be spermine or spermidine and pharmaceutically acceptable salts, solvates or
polymorphs thereof.
7. The composition of any one of paragraph 1 to 6, wherein the composition comprises
an effective amount of the a 6-mercaptopurine ribonucleoside analogue and the effective
amount comprises an amount between 0.5 mg of the analogue per 1 kg of subject to 3 mg of
the analogue per 1 kg of subject.
8. The composition of any one of paragraph 1 to 7, further comprising a second anti-
cancer agent.
9. The composition of any one of paragraph 1 to 8, further comprising a second
pharmaceutical composition comprising a second anti-cancer agent, wherein the
pharmaceutical composition is administered in a first stage of treatment and the second
pharmaceutical composition is administered in a second stage of treatment, wherein the
second pharmaceutical composition is administered in a first stage of treatment and the
pharmaceutical composition is delivered in a second stage of treatment, or wherein the first
pharmaceutical composition and the second pharmaceutical composition are administered on
the same day or simultaneously.
10. The composition of any one of paragraphs 8 and 9, wherein the anti-cancer agent
comprises a telomerase inhibitor.
11. The composition of any one of paragraphs 8 and 9, wherein the anti-cancer agent
comprise imetelstat sodium.
12. The composition of any one of paragraphs 1 to 11, wherein an effective amount of the
pharmaceutical composition is administered at least twice per week for at least 2 weeks, at
least 4 weeks, at least 6 weeks, at least 8 weeks, or at least 12 weeks.
13. The composition of any one of paragraphs 1 to 12, wherein the pharmaceutical
composition can be injected or administered orally.
14. The composition of any one of paragraphs 1 to 13, wherein the size of a tumor is
reduced or the growth rate of the tumor is reduced.
. A method for treating a subject in need thereof comprising administering to a subject
a pharmaceutical composition comprising a 6-mercaptopurine ribonucleoside analogue,
wherein the subject has been diagnosed with cancer or a hyperproliferative disease.
16. The method of paragraph 15, wherein the 6-mercaptopurine ribonucleoside analogue
comprises 6-thio-2’-deoxyguanosine.
17. The method of paragraph 15, wherein the 6-mercaptopurine ribonucleoside analogue
is a compound according to the following formula:
where R can be an H, hydroxyl group, an amino group, an alkyl amino group, a fluoride, an
acyl group, a C -C alkyl or ether group, a phosphate, diphosphate, triphosphate,
1 20
phosphonate, or a phosphodiester group; where R’ can be an H, a hydroxyl group, flouride
group, a C -C alkyl or ether group; where R” can be a hydroxyl group, a flouride, or an
1 20
amino group in the ribo or arabino configuration; where R can be an amino group or a alkyl-
amino group; and pharmaceutically acceptable salts, solvates or polymorphs thereof.
18. The method of paragraph 15, wherein the 6-mercaptopurine ribonucleoside analogue
is a compound according to the following formula:
where R can be an H, an acyl group, a C -C alkyl or ether group, a phosphate, diphosphate,
1 20
triphosphate, phosphonate, or a phosphodiester group; where R’ can be an H, a hydroxyl
group, flouride, a C -C alkyl or ether group; where R” can be a hydroxyl group, a flouride,
1 20
or an amino group in the ribo or arabino configuration; where R can be an amino group or a
alkyl-amino group; and pharmaceutically acceptable salts, solvates or polymorphs thereof.
19. The method of paragraph 15, wherein the 6-mercaptopurine ribonucleoside analogue
is a compound according to the following formula:
where R can be an H, -C(O)(CH ) CH where n = 6-16 and pharmaceutically acceptable
2 n 3
salts, solvates or polymorphs thereof.
. The method of paragraph 15, wherein the 6-mercaptopurine ribonucleoside analogue
is a compound according to the following formula:
where R can be spermine or spermidine and pharmaceutically acceptable salts, solvates or
polymorphs thereof.
21. The method of any one of paragraphs 15 to 20, wherein an effective amount of the
pharmaceutical composition is administered to the subject per day and the effective amount
comprises an amount between 0.5 mg of the analogue per 1 kg of subject to 3 mg of the
analogue per 1 kg of subject.
22. The method of any one of paragraphs 15 to 21, further comprising the step of
administering to the subject a second pharmaceutical composition comprising an anti-cancer
agent.
23. The method of paragraph 22, wherein the pharmaceutical composition is delivered in
a first stage of treatment and the second pharmaceutical composition is delivered in a second
stage of treatment.
24. The method of paragraph 22, wherein the second pharmaceutical composition is
delivered in a first stage of treatment and the pharmaceutical composition is delivered in a
second stage of treatment.
. The method of paragraph 22, wherein the first pharmaceutical composition and the
second pharmaceutical composition are administered on the same day or simultaneously.
26. The method of any one of paragraphs 22 to 25, wherein the anti-cancer agent
comprises a telomerase inhibitor.
27. The method of any one of paragraphs 22 to 25, wherein the anti-cancer agent
comprise imetelstat sodium.
28. The method of any one of paragraphs 22 to 27, wherein an effective amount of the
pharmaceutical composition is administered at least twice per week for at least 2 weeks, at
least 4 weeks, at least 6 weeks, at least 8 weeks, or at least 12 weeks.
29. The method of any one of paragraphs 15 to 28 wherein the pharmaceutical
composition is administered orally or injection.
. The method of any one of paragraphs 15 to 29, wherein the pharmaceutical
composition is administered by intratumoral injection
31. The method of any one of paragraphs 15 to 30, wherein the size of a tumor is reduced
or the growth rate of the tumor is reduced.
32. The method of paragraph 15, wherein the subject is a human being.
Claims (18)
1. Use of 6-thio-deoxyguanosine (6-thio-dG) in the manufacture of a medicament for treating a telomerase-expressing cell characterized by an over-activation of 5 telomerase in a subject, wherein the medicament does not include a telomerase inhibitor.
2. The use of claim 1, wherein the medicament comprises an effective amount of the 6-thio-dG and the effective amount comprises an amount between 0.1 mg of 6-thio- 10 dG per 1 kg of subject to 50 mg of 6-thio-dG per 1 kg of subject per day.
3. The use of any one of claims 1 to 2, wherein the medicament further comprises a second anti-cancer agent, and wherein the second anti-cancer agent is not a telomerase inhibitor.
4. The use of any one of claims 1 to 3, further comprising use of a second anti- 15 cancer agent in the manufacture of a second medicament, wherein the second anti- cancer agent is not a telomerase inhibitor, wherein the medicament is formulated for administration in a first stage of treatment and the second medicament is formulated for administration in a second stage of treatment, wherein the second medicament is formulated for administration in a first stage of treatment and the medicament is 20 formulated for administration in a second stage of treatment, or wherein the medicament and the second medicament are formulated for administration on the same day or simultaneously.
5. The use of any one of claims 1 to 4, wherein an effective amount of the medicament is formulated for administration at least twice per week for at least 2 25 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, or at least 12 weeks.
6. The use of any one of claims 1 to 5, wherein the medicament is formulated for injection or oral administration.
7. The use of any one of claims 1 to 6, wherein administration of the medicament reduces the size of a tumor or the growth rate of the tumor.
8. The use of any one of claims 1 to 7, wherein the size of a tumor is reduced or the growth rate of the tumor is reduced.
9. A method of treating a telomerase-expressing cell characterized by an over- activation of telomerase in a non-human subject comprising administering a 5 pharmaceutical composition comprising 6-thio-deoxyguanosine (6-thio-dG) to the non-human subject, wherein the pharmaceutical composition does not include a telomerase inhibitor.
10. The method of claim 9, wherein the pharmaceutical composition comprises an effective amount of the 6-thio-dG and the effective amount comprises an amount 10 between 0.1 mg of 6-thio-dG per 1 kg of subject to 50 mg of 6-thio-dG per 1 kg of subject per day.
11. The method of claim 9 or 10, further comprising administering a second anti- cancer agent, wherein the second anti-cancer agent is not a telomerase inhibitor.
12. The method of any one of claims 9 to 11, further comprising administering a 15 second pharmaceutical composition comprising a second anti-cancer agent, wherein the second anti-cancer agent is not a telomerase inhibitor, wherein the pharmaceutical composition is administered in a first stage of treatment and the second pharmaceutical composition is administered in a second stage of treatment, wherein the second pharmaceutical composition is administered in a first stage of treatment 20 and the pharmaceutical composition is administered in a second stage of treatment, or wherein the pharmaceutical composition and the second pharmaceutical composition are administered on the same day or simultaneously.
13. The method of any one of claims 9 to 12, wherein an effective amount of the pharmaceutical composition is administered at least twice per week for at least 2 25 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, or at least 12 weeks.
14. The method of any one of claims 9 to 13, wherein the pharmaceutical composition is administered orally or by injection.
15. The method of any one of claims 9 to 14, wherein administering the pharmaceutical composition reduces the size of a tumor or the growth rate of a tumor.
16. The method of any one of claims 9 to 15, wherein the size of a tumor is reduced or the growth rate of the tumor is reduced.
17. The use according to any one of claims 1 to 8, substantially as herein described with reference to any example thereof and with reference to the accompanying 5 figures.
18. The method according to any one of claims 9 to 16, substantially as herein described with reference to any example thereof and with reference to the accompanying figures.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361809575P | 2013-04-08 | 2013-04-08 | |
US61/809,575 | 2013-04-08 | ||
NZ713498A NZ713498A (en) | 2013-04-08 | 2014-04-08 | Mercaptopurine ribonucleoside analogues for altering telomerase mediated telomere |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ732228A NZ732228A (en) | 2020-11-27 |
NZ732228B2 true NZ732228B2 (en) | 2021-03-02 |
Family
ID=
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