Professional Documents
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FACULTY OF SCIENCE
MODULAR DEGREE SCHEME
K0433939
CANCER
– BIOLOGY OF CANCER
– CANCER CAUSES
– CANCER TYPES
– GENES IN CANCER
– TREATMENT SCHEMES
P-GLYCOPROTEIN
– HISTORY
– STRUCTURE
– DRUG RESISTENCE
CONCLUSION
REFERENCES
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
ABSTRACT
influence. The membrane bound MDR1 gene product P-glycoprotein (Pgp) has been
research has strived to modulate the effects of Pgp or more recently make use of this
Background
According to the World Health Organisation (WHO), cancer is a leading cause of
death worldwide and accounts for an estimated 7.4 million deaths (2004 statistics),
13% of all deaths worldwide. Cancer can affect any part of the body and there are
In the U.K alone there are approximately 285,000 new cases of cancer diagnosed
each year and it is estimated that 1 in 3 people will develop some form of cancer in
with 75% of cases developing in people at the age of 60 and above. Cancers in
children, teenagers and young adults account for approximately 1% of all cases.
Although cancer incidence has remained relatively stable over the last decade there
has been an overall increase in incidence rates in the U.K constituting a rise of one
deaths per
year
Lung 1.3 million
The WHO projects deaths from cancer worldwide to continue rising with an estimated
12 million deaths worldwide in 2030. Both men and women are affected however
variations exist between genders for the most frequent types of cancer.
Among men lung cancer is the most prevalent whereas breast cancer dominates
cancer incidences among women (Table 1). In the U.K the overall cancer death rates
have fallen by about 10% however a staggering 150,000 deaths, 1 in 4 of all deaths
are as a result of cancer (Figure 1). Despite declines in death caused by uterine,
oesophageal and male skin cancer 1 in 5 cancer fatalities are attributed to lung
cancer.
projected increases (12 million by 2030) place an ever mounting challenge on the
Biology of Cancer
“Tumors destroy man in a unique and appalling way, as flesh of his own flesh which
Yet, despite more than 70 years of experimental study, they remain the least
Peyton Rous, in his acceptance lecture for the Nobel Prize in Physiology or Medicine
(1966)
Cancer refers to group of diseases that develop across time and are predominantly
characterised by uncontrolled division of the body’s cells. In the case of normal cells
external growth factors are required to instruct the cell to divide. Normal cell
regulation inhibits these growth factors accordingly and halts further division. Cancer
cells operate independently of these positive growth factors and thus divide in their
Cancerous cells begin to dictate their own agenda for proliferation. Not only does this
ancestral cell display inappropriate proliferation all of its subsequent progeny operate
in this manner a mass of cells formed of these abnormal cells are referred to as a
tumour which can either stay in the tissue it originated in ( in situ cancer) or it may
begin to invade nearby tissue (invasive cancer). Invasive tumors are said to be
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
malignant. National Institutes for Health., (1999)., Normal cells can divide to fill in a
gap but a soon as there are a sufficient number of cells to fill the gap they cease to
divide. Cancer cells show no contact inhibition and continue to divide after they touch
other cells and consequentially form this large mass of cells -tumour. Blackburn et
al.,
Cells have a lifespan and this entails ageing and death via apoptosis which is the
normal, regulated programmed death of cells. Their ability to replicate their DNA is
limited to approximately 50 times due to the fact that each time a chromosome
replicates the (ends) shorten. Growing cells utilise telomerase enzymes to replace
lost cells whereas maturet cells lack this enzyme resulting in their limited replications.
Cancerous cells have the ability to activate telomerase in adult cells and this allows
for an unlimited number of cell divisions. Columbia Encyclopaedia 6th edition., (2007)
divide and since cancerous cells divide regardless of DNA damage or abnormal cell
Blackburn et al.,
puts pressure on surrounding organs and tissue or cancer cells metastasize and
environment conducive to further mutation. This applies to virtually all of the body’s
cancerous cells attain a selective advantage over normal proliferating cells and thus
to acquire the traits together and manifest into a malignant growth of cells. National
Institutes for Health., (1999)The main functioning genes are subdivided into three
categories. Proto-oncogenes produce proteins that enhance cell growth and division.
When mutated these genes are referred to as oncogenes. The second group are the
tumour suppressor genes and these create proteins that terminate cell division and
induce apoptosis. The third group are genes coding for DNA repair mechanisms
which help repair DNA from molecular changes that lead to cancer. National
Mutations in any three of the groups of genes potentiate the development of cancer
(Table 2).
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
Table 2: Gene mutations and their implications
accelerated and
uncontrolled growth
Tumour suppressor genes Limited ability of signalling
inhibitory messages
alterations in DNA
Genes in Cancer
Modern science views on cancer centre around it being a multistep process
changes precancerous cells manage to acquire the traits together and manifest into
excessive division whilst mutations in tumour suppressor genes (figure 4), results in
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
their inactivation. Consequentially the ability to inhibit excessive growth is lost and
collectively mutations in these groups of cancers account for most human cancers.
Proto-oncogenes code for proteins that play a part in pathways that process and
receive growth signals (figure 3) from other cells within a particular tissue. When
growth factors
Blackburn et al,.
are produced they move into the gaps between cells attaching to specific receptors
proteins within the cell cytoplasm. These proteins in turn convey these messages
stimulating other proteins all the way to the nucleus and activate genes that facilitate
the movement of the cell through its growth cycle. The mutated form of these genes
overactive and as a result cell proliferation progresses at much faster rate than in
comparison to the rate before the mutation. Oncogenes also produce deviating
Blackburn et al,.
damaged errors in the DNA go unattended. Without DNA mechanisms mutations are
allowed to accumulate within the cell. These mutations increase the cancerous
CANCER CAUSES
There maybe multiple mechanisms leading to the development of cancer (figure 5).
Although disputed the prevailing model centres around mutations occurring within
indicate mutations occurring in “master genes” which control the cell cycle and that
once a mutation occurs in these genes inappropriate gene dosing occurs. As a result
of this cells produce too much or too little of particular proteins required for proper
cell growth and an imbalance of this sort leads to cancer. Blackburn et al,.; National
Viruses that affect humans may also promote cancer; this is the case with viruses
which insert their DNA into the chromosome at the same point in which proto-
oncogenes are located thus inactivating them (converting them into oncogenes).
Virus DNA located close to genes involved in the regulation of cell growth may take
(inappropriately) which provides the possibility of a cancer occurring. The table below
shows a few viruses that have been implicated in cancer. Blackburn et al,.
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
cancer
Human papillomavirus Genital Carcinomas
cell lymphoma
Cancer research over the years had lead to knowledge that environmental factors
that there was an unusually high incidence of scrotal cancer amongst men who
from X-rays, UV light, Tobacco smoke, industrial solvents. Some cancers associated
with these factors are not associated with cancer genes furthermore some are
based on where the original alteration occurred (See Table 4 below). Blackburn et al,.
Type Origin
Carcinoma Epithelial cells (most common)
connective tissue
system)
Myeloma Specialised anti-body
TREATMENT SCHEMES
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
The basis of medical cancer therapy falls under the categories of chemotherapy,
Surgery -ectomy
Chemotherapy is one of the mainline treatments in cancer and involves the use of
cells consistent with tumour growth with a 90% efficacy on 10% of all cancers
Roylance 2007. They are however non-specific to tumour cells thus normal cells my
VINCA
PHASE NON-SPECIFIC
ALKALOIDS
Alkylating agents
TAXANES
Cisplatin
Nitrosoureas
Antibiotics
M
G0
G2 G1
S
METHOTREXATE
HYDOXYUREA
CYTOSINE ARABINOSIDE
ANTHRACYCLINES
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
Roylance 2007
Combination chemotherapy involves using more than 1 class of chemotherapeutic
agent at optimal dose and schedule. This enables synergistic action of the drugs as
different drug classes will affect different points within the cell cycle (figure 6).
cells are damaged in the process. Unlike chemotherapy these cells have the ability to
It involves the use of ionising radiation in measured doses (X-rays). This radiation
damages cells hindering their growth and division. It is usually given before and after
surgery to reduce tumour size and after to improve treatment results. Palliative
Hormonal therapy is usually associated with breast and prostate cancer and it is a
relatively specific form of treatment with minimal toxicity. Beaston 1896 postulated a
link existed between the ovaries and the proliferation of breast cells after removing
the ovaries of a woman with advanced metastatic breast cancer, she responded
contraceptive its uses in breast cancer soon superseded its relatively low efficacy as
a contraceptive (it even induced ovulation in some cases). In 1973 it was licensed for
use in breast cancer and its mechanism of action (Jordan 1974) involved the
Biological therapy involves the use of monoclonal antibodies and small molecule
inhibitors. This strategy is efficacious however the mechanism of action is not fully
understood. The treatment is specific and of minimal toxicity (e.g. herceptin). This is
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
a relatively novel treatment strategy in cancer thus many of the treatment regimes
are not implemented unless conventional treatment has failed. Roylance (2007)
P-GLYCOPROTEIN
P-glycoprotein (Pgp) is the most characterised member of the human ATP Binding
Cassette (ABC)-transporter family. It is the gene product of the MDR1 gene and
serves as an integral efflux membrane protein. Pgp and members of this superfamily
are characterised by the ATP driven active transport of substances out of the cell. It
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
is believed to have evolved as a protective mechanism against harmful toxins
Landwojtowicz (2000)
The ABC efflux transporters are primarily located in plasma membranes; here they
Schinkel and Jonker (2002). The human genome codes approximately 48 ABC
proteins, which are subdivided into subfamilies via sequence alignments (From A to
subunits. These proteins are membrane bound consisting of various domains and
Szakacs et al 2008
Pgp transports a variety of chemically diverse substances across the cell membrane
thus protecting the cell from passively transported drugs. It plays a role in the
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
bioavailability of substances that enter the cell (including drugs, metabolites, and
xenobiotics). This wide substrate specificity limits compounds crossing tissues with a
protective barrier function which include; blood-brain barrier, liver, intestines, kidney
and testis/placenta (Figure 4). Most Pgp substrates are hydrophobic and many of
them contain aromatic ring structures Endicott and Ling (1989); Gottesman and
Pastan (1993). Its substrate specificity extends to non cytotoxic compounds as well;
drugs.
P-gp History
Juliano and Ling (1976) first characterised P-gp while working with Chinese hamster
ovary (CHO) clonal cell lines where they reported the expression of a protein (P-gp)
(1974) (figure7) in which they isolated a series of related colchicine resistant CHO
clonal cell lines using single step selections. They also found that increasing
uptake.
The isolation of clones using Chinese hamster ovary (CHO) cells (Juliano and Ling
1976) was useful as a method of investigating somatic cell mutations and the
environmental mutations.
mutations are valuable as they can also serve as genetic markers. Single step
whether the appearance of variants was consistent with spontaneous mutation rates.
In 1970 while assessing the resistance of murine leukaemia sublines (L5178Y and
50µg/kg actinomycin D inhibited uridine incorporation into RNA in L5178Y but not in
These findings concurred with those of other researchers at the time and during the
of colchicine was proportionate to the degree of drug resistance. This led to the
permeability.
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
Juliano and Ling (1976) attributed the multi-drug resistant characteristic of tumor
cells as being brought about by the overexpression of this surface glycoprotein and
STRUCTURE OF P-GP
The structure of Pgp like other functional entities of ABC transporters consists of 4
domains.2 membrane domains (MDs) and 2 nucleotide binding domains (NBDs also
referred to as the ATP-binding cassettes). The NBDs are responsible for the
generation of motional force while the MDs provide a translocation pathway for
substrates bound to the protein. Pgp shares a number of conserved sequence motifs
with other ABC transporters (Walker A, Walker B and the ABC signature) due to ATP
their common substrate. MDs however are more diverse and this diversity is
reflected by the large diversity of substrates that are transported. Seeger and W. van
Veen ( 2008)
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
Figure 8a: P glycoprotein structure
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
Schinkel and Jonker 2003
glycosylation occurring on the first loop. The NBDs or similarly the ATP binding
cassettes are located intracellularly (Figures 8a and 8b). In vitro studies on Pgp
structure Schinkel et al (1993) showed that N-glycosylation was not necessary for
basic transport function. Up to 3 sites present in the mdra1 protein, they also deleted
transfection into drug-sensitive cells the effects of the mutations were analysed. It
was found that the absence of N-glycosylation did not alter the level or pattern of
clones where generated. As a result of these findings it was postulated that the
show that following the passive diffusion of chemical agents into the cell
cytoplasm they are bond by Pgp and exported out into the extracellular space
Theibaut et al 1987
Thiebaut et al ‘s findings support the hypothesis of the MDR1 gene product (P-gp) as
agents.
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
DRUG RESISTANCE
“The first successful chemotherapy of human cancer led soon to the realization that
diagnosed with leukaemia in what was the beginnings of modern age treatment to
caner. This also symbolised the beginnings of the understandings of drug resistance
and its clinical consequences as the treated children experienced an initial response
expected to reduce tumour size in 50% of all cases. In almost all cases drug
resistance develops and is the major cause of fatalities Baird and Kaye (2003).
efficacy in patients with intrinsic resistance which is present at the time of diagnosis
transporter protein.
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
excretion are some of the factors that lead to drug resistance. Alterations in cancer
cells can lead to increased drug efflux (ABC transporters; Pgp), decreased drug
multiple myeloma found that the frequency of Pgp expression increased after
chemotherapy (Fig 6 ).
Despite the extensive cataloguing of Pgp expression in many cancer types a clear
relationship between Pgp detection and its implications on prognosis and response
to therapy is still debated. Poor design of clinical trials and a general lack of
included:
(a) Although detection of Pgp and MDR1 is at present likely to be more reliable in
leukemias and lymphomas than in solid tumors, accurate measurement of low levels
(b) Tissue-specific controls, antibody controls, and standardized MDR cell lines are
essential for calibrating any detection method and for subsequent analyses of clinical
samples;
(g) Arbitrary minimal cut-off points for analysis compromise the reliability of
conclusions
Beck et al (1996)
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
chemotherapy and is the main reason for failure of treatment Aouali et al (2005). One
(vincristine in particular) was the calcium channel blocker Verapamil . This was
resistance patterns from bone marrows from 59 myeloma patients and found that
doxorubicin and vincristine in vitro but did not enhance sensitivity of cells that were
drug sensitive (P>.001). Clinical trials were then conducted on 22 patients with
administered with i.v verapamil. The clinical efficacy of the trials prompted the
toxicity however was observed in some patients (fig 9), an unacceptable routine for
Salmon et al 1991
The use of verapamil, cyclosporine Yahanda et al (1992) and other 1stgeneration Pgp
block Pgp activity and by clinically significant toxicity profiles. These findings
modulator for Pgp. Their findings proposed that a Pgp modulator candidate should
have
(P version 4.0 QSAR software and HyperChem version 5.0 program) (Wang et al
2003)
Zamora et al 1988 and Wang et al 2003 the pharmacophoric parameters lacked the
generation modulators had shown efficacy and thus they formed the template of
For a compound to eligible as a modulator of Pgp it must fulfil at least one of the
following criteria:
resulted in high levels of toxicity and a major contributing factor to this was the low
binding affinities observed which prompted higher doses. The clinical application of
al (1992).
Manetta et al 1993 conducted phase I trials in which the potential clinical use of
cyclosporine A modulation of cisplatin was investigated, they also set out to identify a
20% of patients developed nephrotoxicity with 25% of the patients being partial (3
new compounds. Analogues of these agents where developed and these included
dexverapamil, dexniguldipine, PSC 833 and VX-710. Wilson et al 1995 reported 10-
20fold greater activity. Many studies show it to have high reversing potency Boesch
material from patients with soft tissue sarcoma recorded modest on accumulation of
ancthracycline (20%) when given at 1nM. Animal models of 2nd Pgp generation
modulators show significant results Watanabe et al 1996 however clinical trials show
evidence of limited success. VX710 like PSC 833 has been extensively studied. It
directly interferes with the efflux of substances due to its affinity to the Pgp pump as
well as other related ABC transporters (namely MRP1). The coadministration of this
compound with chemotherapeutic agents has had limited success in the treatment of
the efficacy of VX710 when co administered with doxorubicin and vincristine patients.
The patients suffered from inoperable, local advanced or metastatic sarcoma of the
soft tissue. In addition the patients had anthracycline-resistance. The study was on
36 patients who enrolled over a two year period and of varying demographic. VX710
Neutropenia was also found to be the major toxicity occurring in 26/30 patients in
trials. There was however partial responders 7/36 patients as detected by radiology
results and a halt to the trials. Similarly earlier studies conducted by Bramwell et al
2002 revealed objective responses for the drug with disease stabilisation in partial
2nd generation inhibitors have a better pharmacologic profile than 1st generation
inhibitors however they also posses similar characteristics which limits their chemical
Cytochrome P450 enzymes are also induced along with ABC transporters leading to
suppositions that regulatory elements of these genes overlap Lum and Gosland
1995. The P450 3A4 isoenyme shares many substrates with Pgp thus substances
affected by MDR development are also liable to metabolism by P450 3A4 (PSC 833
and VX710) and thus results in many of the reported unpredictable pharmacokinetic
interactions. These agents inhibit the P450 3A4 mediated metabolism and is the
main cause of toxicity associated with modulators off Pgp. Dose reductions had to be
dosing regime limits the efficacy of many of these 2nd generation modulators.
Furthermore intrinsic activity of some 2nd generation modulators (VX710, PSC 833)
suggests they have affinities for other ABC transporters as well as Pgp and this
inhibitory activity of non-target transporters may contribute to the limited efficacy and
and potently inhibit Pgp function. Their development occurred as a result of structure
relevant concentrations they do not show activity at P450 3A4 enzymes Dantzig et al
1999 where the selectivity of LY335979’s selectivity for Pgp was evaluated as well as
its effects of P450 activities. It was found to have a significantly lower affinity for
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
CYP3A than for Pgp. Furthermore it was characterised as a potent modulator of Pgp
and not other members within the ABC transporter family (namely MPR1 and MPR2).
varying chemical structures but are common in their level of potency on Pgp. This
has also been observed in clinical trials as well the most promising agent of
binding to the ATP binding sites of Pgp. Martin et al 1996; roe et al 1999 findings
identified XR9576 as a potent inhibitor of Pgp in vivo and in vivo. Martin et al 1999
used drug resistant CHO ovary cell lines and demonstrated XR9576 showing greater
selectivity, duration of inhibition and potency of interaction at Pgp than with any other
reported modulators.
paclitaxel transport as high as in cell lines that were not overexpressing Pgp
(EC50=487+50 nM). By binding to the ATP sites means that Xr9576 like most 3rd
with the synthesis of Pgp. This has brought into use antisense oligonuleotides,
ribozymes and protein that regulate differentiation of cancer cells Corrias et al 1992;
Efferth et al 1993. These strategies focus on cleavage of MDR1 mRNA and have the
They transduced these ribozymes into MDR1 expressing cells which were designed
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
to target specific predetermined sites (fig11) in addition a retroviral vector containing
Kobayashi et al 1999
Human leukaemia cell lines (MOLT-3 where MDR subline used was MOLT-3/TMQ800)
where used and these were co-cultured with virus producer cells. Ribozyme efficacy
was then determined by G418 selection and ribozyme transduced cells became
fold more resistant to vincristine whereas stably transduced cells showed 92 to 296-
iMDR1-sRz one of the ribozymes used targeted the translation-initiation site and
carcinoma (A2780) cell lines. Cells exhibiting MDR also had elevated levels of the c-
fos furthermore cells transfected with c-fos also exhibited MDR and the anti-fos
ribozyme reversed the MDR phenotype in A2780AD cells. These studies reveal
play a role in resistance to agents not within the MDR family such as cisplatin, AZT
cells has been explored to protect them from the adverse effects of chemotherapy.
The drug resistance genes may serve as selectable markers in vivo facilitating gene
Licht et al (1998) transferred MDR1 cDNA to mouse bone marrow cells that lacked
expression of lineage –specific antigens nor MHC II antigen Ia. These cell had high
expression of Ly6A/E. Isolated cells were expanded ex vivo using growth factors.
Gene transfer was achieved via coculture containing retrovirus. Functional Pgp was
detected in 60% of expanded cells. The recipient animals expressed Pgp in high
animal models. In normal and also in tumour tissue MDR expression varies greatly
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
whereas in bone marrow cells it remains consistently low. This renders stem cell
etoposide, vinca alkaloids all of which are effect against many cancer forms.
They reported the successful transfer and expression of the human MDR1into
human bone marrow cells (via amphotropic retroviral supernatant) and the resistance
The main MDR producer A12M1 had the highest titer (5 x 1014 viral particles/ mL).
untransduced cells.
Taxol was introduced to MDR-transduced cells and their level of MDR expression
transduction. Analysis took place on day 12 and 12.5% of cells showed increase in
transduced cells and preferential survival was observed in transduced cells at doses
of 5 x 10-8 mol/L. This ability to select for progenitor cells resistant to taxol bears
significant perspective on its potential use in providing drug resistant marrow cells for
marrow populations of cells with the MDR gene and a non-selectable gene (e.g beta-
Be it promising the first published clinical trials conducted on MDR1 levels reported
expression of these transferred genes is the major cause for failure of gene therapy
Takahashi et al 2007
Peripheral blood was stimulated using 5 cytokines; SCF, TPO, IL-6, FL-Ligand & sIL-
Transplantation of induced peripheral blood stem cells (PBSC) (1/3) and untreated
PBSC (2/3) yielded 3-5% increases in the ratio of peripheral white blood cells which
this after 6 months Pgp expressing cells decreased to an undetectable level. These
limited successes in clinical scenarios may indicate low survival chances of MDR1-
transduced stem cells in the bone marrow or may lie in transduction strategies which
Discussion/ Conclusion
Extensive studies have been carried out on the MDR gene and it gene product P-
main role is the expulsion of toxic substances that enter the cells of the body.
The use of radiolabelled dyes monoclonal antibodies have elucidated its distribution
chemotherapeutic agents.
This greater understanding of Pgp gave rise to many pharmacological studies aimed
rapidly. Many agents proved promising however clinical trials yielded limited
successes. A significant trend in these studies was that although Pgp modulators
drug. Alterations of doses and more potent drugs were designed slightly increasing
Research has generally shifted to stem cell biology and gene therapy and significant
progress has been made since the early days of introducing foreign genes into
murine cells via retroviral vectors. Gene therapy directed at transferring resistance to
rapidly declined. This largely due to the limited positive results obtained in clinical
trails to a variety of gene therapy approaches in which low efficiency was reported.
challenges lie ahead in the translation of recent advances into reproducible clinical
benefit.
multicausative. A number of genes have been identified that are associated with
mediated resistance in cancer various other approaches involving other genes are
Any major advances in Pgp modulation or application will have to encompass other
related ABC transporters and other factors contributing to the MDR phenomenon this
therapy.
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
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Acknowledgements
THE BIOLOGICAL AND CLINICAL SIGNIFICANCE OF P-GLYCOPROTEIN IN CANCER
I would like to thank Dr. Helmout Modjtahedi For all his assistance. He