Transcript RET is Dispensable for Maintenance of Midbrain

Cancer Therapy and
Nanotechnology
Presented by Mattia M. Migliore
December 5, 2006
Introduction:

Neoplasms: are defined as a new formation of cell
clusters, which have lost their ability to control cell
division.
 Neoplasms can either be benign or malignant.
 Benign tumors:
1.
2.
3.
4.
5.
Differentiated.
Slow rate of proliferation.
Encapsulated.
Do not infiltrate surrounding tissue.
Usually do not result in patient death.
http://www.scienceclarified.com/images/uesc_10_img0586.jpg
Introduction (cont.):

Malignant tumors:
1. High rate of cell
proliferation.
2. Loss of contact
inhibition.
3. Lack of
differentiation.
4. Grow by invading and
infiltrating.
5. Loss of cohesiveness.
6. Resistance to
apoptosis.
http://www.news-medical.net/images/breast%20cancer%20cell.jpg
http://www.gcarlson.com/images/metastasis.jpg
Estimated Number of Persons Alive in the U.S.
Diagnosed With Cancer by Site (N = 10.5 M)
Prevalence of Cancer type in the US. Data source: 2005 Submission. U.S. estimated cancer prevalence counts were estimated by applying U.S.
populations to SEER 9 and historical Connecticut Limited Duration Prevalence proportions and adjusted to represent complete prevalence.
Populations from January 2003 were based on the average of 2002 and 2003 population estimates from the U.S. Bureau of the Census.
www.cancer.gov.
The Cell Cycle and Cancer:

Cell proliferation is a tightly controlled
process that ensures the accurate
replication and transcription of genetic
information.
 Genetic mutations can either be repaired,
or result in the induction of apoptosis.
 Mutations in certain genes, called
oncogenes, can result in dysregulation of
the cell cycle, resistance to apoptosis, and
in the development of cancer.
 A large number of today’s most effective
cancer treatments are cytotoxic agents that
target the cell cycle.
http://nobelprize.org/nobel_prizes/medicine/laureates/2001/press.html
HISTORY OF CANCER THERAPY :
(Chabner and Roberts, 2005)
Current Cancer Treatment Strategies:



Surgery: The first line of
treatment for solid tumors, and
may be curative if the tumor
has not metastasized.
Radiation Treatments: Uses
ionizing radiation.
Chemotherapeutic Agents:
Three main classes of
cytotoxic drugs used to treat
neoplastic disease. The
alkylating agents, the
antimetabolites, and the natural
products.
http://www2.slac.stanford.edu/vvc/art/schematic.gif
Current Cancer Treatment Strategies (cont.):
1)
2)
.
http://www.ovc uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-409/
Cancer/Cancer_images/Nitrog_must.gif
http://www.wellesley.edu/Chemistry/chem227/nucleicfunction/cancer/methotrexate.gif
Alkylating agents: Form covalent
bonds on double stranded DNA,
and prevent transcription.
Activation of DNA repair
mechanisms result in DNA strand
breaks, and in apoptosis.
Antimetabolites: Most effective
during the S phase of the cell
cycle. Include the folic acid
analogs (ex. methotrexate),
pyrimidine analogs (ex.
fluorouracil), and purine analogs
(ex. mercaptopurine). Their
mechanisms of action are to inhibit
DNA synthesis, and/or to inhibit
transcription and translation.
Current Cancer Treatment
Strategies (cont.):
3) Natural Products: include the
vinca alkaloids (ex. vincristine),
taxanes (ex. paclitaxel), and
epipodophyllotoxins (ex.
etoposide). Mechanisms of
action include DNA
intercalation, inhibition of DNA
and RNA synthesis, inhibition
of topoisomerase, free radical
production, and inhibition of
microtubule formation.
http://en.wikipedia.org/wiki/DNA_intercalation
Current Cancer Treatment Strategies (cont.):


http://www.orienttumor.com/english/MT/PDT/002_s.jpg
http://www.gene.com/gene/research/images/angiogenesis.jpg

Photodynamic Therapy: Uses a
photosensitizing drug (porfimer
sodium).
Hormonal treatments: For
certain types of tumors.
Angiogenesis Inhibitors: Inhibit
tumor vascularization. The first
FDA approved angiogenesis
inhibitor was bevacizumab,
which is a humanized
monoclonal antibody against
vascular endothelial growth
factor (VEGF).
Current Cancer Treatment Strategies (cont.):

Tyrosine Kinase Inhibitors:
Inhibit DNA synthesis and/or
gene transcription. There are
currently three FDA approved
tyrosine kinase inhibitors:
Imatinib, gefitinib, and erlotinib.
 Biological Response Modifiers
(BRMs): Enhance the body’s
ability to effectively fight cancer,
or they minimize chemo side
effects. BRMs include
interferons, interleukins, colonystimulating factors, monoclonal
antibodies, and vaccines for the
prevention of certain types of
cancer.
http://www.amn107.com/images/aee788Large.jpg
Nanotechnology in the Treatment of Cancer:


Nanotechnology has generated a great
deal of interest in the field of
oncology due to its potential to
selectively deliver and concentrate
drugs to tumors while minimizing
damage to healthy cells.
Two FDA approved nanoparticle
formulations for the treatment of
cancer:
1. Abraxane®: a suspension of
albumin-bound paclitaxel (130 nm).
FDA approved in January, 2005.
2. Doxil®: liposomal formulation of
doxorubicin (100 nm). Approved in
February, 2005.
http://www.abraxane.com/images_charts/vhs_tape_box.gif
http://www.doxil.com/images/clientChart.gif
Nanoparticle drug-delivery systems under
development for the treatment of cancer :

Adriamycin-loaded nanoparticle formulation: In vivo studies
demonstrated superior efficacy. In this study, rats were implanted with
liver tumors and were later treated with either adriamycin alone, or with
adriamycin-loaded nanoparticles (average diameters of 93 nm) injected
directly into the hepatic artery (Chen et al., 2004).
 Paclitaxel-loaded gelatin nanoparticles: These nanoparticles showed
significant activity against a bladder cancer cell line in vitro (Lu et al.,
2004).

Hydrolysable polymeric micelle system: Engineered with a
hydrolysable segment that confers it a longer degradation half-life, and
which makes it more stable when administered intravenously. A longer
circulation half-life may result in greater tumor drug deposition, and in
greater cytotoxic effectiveness (Zeng and Pitt, 2006).
Nanoparticle drug-delivery systems under
development for the treatment of cancer (cont.):

Dendrimers: Under investigation for the
delivery of oligonucleotides to cancer cells
for gene therapy. Dendrimers, ranging in
130-280 nm in size, were demonstrated to
increase oligonucleotide uptake by 14 fold in
an in vitro breast cancer cell line
(Santhakumaran et al., 2004).

Nanocells: A new nanoparticle drug-delivery
system that makes it possible to combine
drugs with different mechanisms of action in
the same particle, and to design their
temporal release. These nanocells have an
outer pegylated-phospholipid blockcopolymer containing an antiangiogenic drug
(combrestastatin), and an inner nanoparticle
core containing a cytotoxic drug
(doxorubicin) (Sengupta et al., 2005).
Nanoparticles: Scientists Work
on an Anti-Cancer Smart Bomb
imagine a cancer drug that can
burrow into a tumour, seal the
exits and detonate a lethal dose
of anti-cancer toxins, all while
leaving healthy cells
unscathed. MIT researchers
have designed
a nanoparticle to do just that.
MEDICA.de; Source: Massachusetts Institute of Technology
Nanoparticles in the Treatment of Cancer:

Nanoparticles themselves can also be used to destroy
cancer cells directly.
 Metal nanoparticles, together with near infrared light,
have been shown to increase cell death in tumors by
generating hyperthermia (Hirsch et al., 2003).
 Gold nanoparticles inhibit angiogenesis by binding to
vascular endothelial growth factor and basic fibroblast
growth factor and preventing them from activating their
receptors (Mukherjee et al., 2006).
Conclusions:

The search for effective cancer treatments has evolved
over the years from a non-specific screening approach,
to a molecular mechanism-driven targeted approach.
 Nanoparticles hold great potential as drug-delivery
carriers, and as selective cytotoxic agents against
carcinogenic cells.
 Preliminary results indicate that the future of cancer
treatment will include nanoparticles.
 However, more studies are still needed to demonstrate
the superior effectiveness, and diminished toxicity of
nanoparticles.