MOLECULAR TARGETED THERAPY OF CANCER: THE PROGRESS AND FUTURE
PROSPECT
ARTICLE
Primary tumours and large metastases often depend on surgery and radiation therapy.
Traditional anticancer chemotherapy agents block cell division and DNA replication. Many of these
agents could also target the microtubule dynamics of the mitotic spindle.
These early anticancer drugs such as platinum derivatives, nucleoside analogues, topoisomerase
inhibitors, taxanes and vinca alkaloids are widely used today.
Complementary treatment modalities other than chemotherapy:
- molecular therapy
- anti-angiogenesis therapy
- immunotherapy
- apoptosis regulation
- signal-transduction therapy
- differentiation therapy
- targeted radionuclide therapy
- nucleic acid-based therapies
Targeted treatment exerted its anticancer effects through multiple mechanisms, including proliferation
inhibition, apoptosis induction, metastasis suppression, immune function regulation and multidrug
resistance reversal.
Drugs targeting signalling oncoproteins that have gained tumour-driving function through mutations or
overexpression are subsequently developed to increase specificity and thus reduced the side effects,
but have limitations such as the formation and development of drug resistance.
Resistance of therapeutic agents in an important problem in the treatment of cancer disease that is
believed to influence the effectiveness of targeted therapies and the prognosis of patients with cancer.
Although a patient initially was sensitive to some chemotherapeutic agents, he may also acquire cross-
resistance during treatment.
Several mechanism involve in anticancer resistance, including an increase in drugs efflux, alteration or
mutation of drug targets, drug detoxification and inactivation, impact on apoptosis, interference with
DNA replication and other ways.
Molecular Targeted Therapy in Anticancer
The cellular targets are genetically altered in cancer cells and are essential to tumour development and
survival.
Oncoprotein or oncogenes targets, which are mainly involved in various signalling pathways are
primarily products of gene fusions, obtained or functional mutations or overexpressed oncogenes.
Mechanisms of Anticancer Drug Resistance
Several mechanisms involved in resistance to anticancer drug, including an increase in drug efflux,
alteration or mutation of drug targets, drug detoxification and inactivation, impact on apoptosis,
interference with DNA replication and many other ways.
Expression of Drug Efflux Pumps
Multidrug resistance (MDR) occurred at the beginning of the treatment or during treatment when cells
resist to the treatment.
One of the mechanism was the increased expression of drug efflux pumps, such as P-glycoprotein (P-
gp) which is one of the ATP-binding cassette (ABC) transporters and was encoded by the MDR1
(ABCB1) gene.
P-gp become a target of several studies to identify novel compounds to counteract MDR.
, Alteration or Mutation of Drug Targets
Generally, the mutations of functional targets or some alterations of expression levels dramatically
influenced drug resistance.
New anticancer drugs that targeted oncogenic signalling pathways have been developed (cetuximab
and panitumumab).
The specific mutations in the EGFR gene of NSCLC are corelated with clinical responsiveness to the
TKI gefitinib. These mutations lead to the increase of growth factor signalling and susceptibility to the
inhibitor. Such mutations in NSCLC lead to the good response to cetuximab and panitumumab that
could bind to the extracellular domain of EGFR.
Drug Detoxification and Inactivation
Tumor resistance may be present at the beginning of treatment, develop during treatment, or become
apparent on re-treatment of the patient.
Clonal selection in this process was that cell lines produced highly resistant sub-clones on the low
concentrations of drugs exposure.
However, cells may be able to adapt by regulation of expression of resistance or target molecules
individually if they survived the initial exposure to the drug and did not require clonal selection.
This required changes in molecular levels such as epigenetic change and mutilation mechanisms.
Glutathione S-transferase was important for the development of drug resistance via direct
detoxification. It may decrease the concentration of anticancer drugs via the glutathione (GSH)-
conjugate export pump and special emphasis has been put on the function of GSTs in Phase II
detoxification.
Impact on Apoptosis
o The suppression of apoptosis is one mechanism by which tumour cells become drug resistant.
o Why cytotoxic drugs fail to kill sufficient tumour cells in the major human solid cancers, such as the
carcinomas, was suggested to be to the inherent inability of these cells to engage apoptosis after drug-
induced damage.
o Drug resistance mediated by anti-apoptosis is also a key MDR mechanism. B-cell
leukemia/lymohoma-2 (BCL-2) was one of the primary anti-apoptotic proteins.
o The BCL-2 family of proteins regulated cell fate by controlling the mitochondrial apoptotic pathway.
When activated, the pro-apoptotic members Bak and Bax could form high molecular weight oligomers
on the mitochondrial membrane potential and allowed the release of cytochrome to the cytoplasm and
consequently activating the caspases.
o JLP119 B lymphoma cells underwent apoptosis after the exposure to the topoisomerase II inhibitor
etoposide and this was dramatically reduced when the cells were cultured in the germinal centre
system.
Interference with DNA Replication
- On the stress of DNA damage of cancer cells by chemotherapeutic agents, cancer make changes in
some genes to produce the mutator phenotype.
- The obtaining of further mutations could repair DNA damage to make resistance to drug agents.
Irinotecan promoted cancer cell death by interfering with the topoisomerase type 1b enzyme (TOP1)
on DNA, generating cytotoxic protein-linked DNA breaks (PDBs).
- Topoisomerase-II was the primary target for various anticarcinogens. Through forming drug-Topo-II
complexes in cancer cells, these agents promoted DNA strand breaks and affected DNA replication.
Decreased sensitivity and activity of Topo-II were important in the development of drug resistance.
PROSPECT
ARTICLE
Primary tumours and large metastases often depend on surgery and radiation therapy.
Traditional anticancer chemotherapy agents block cell division and DNA replication. Many of these
agents could also target the microtubule dynamics of the mitotic spindle.
These early anticancer drugs such as platinum derivatives, nucleoside analogues, topoisomerase
inhibitors, taxanes and vinca alkaloids are widely used today.
Complementary treatment modalities other than chemotherapy:
- molecular therapy
- anti-angiogenesis therapy
- immunotherapy
- apoptosis regulation
- signal-transduction therapy
- differentiation therapy
- targeted radionuclide therapy
- nucleic acid-based therapies
Targeted treatment exerted its anticancer effects through multiple mechanisms, including proliferation
inhibition, apoptosis induction, metastasis suppression, immune function regulation and multidrug
resistance reversal.
Drugs targeting signalling oncoproteins that have gained tumour-driving function through mutations or
overexpression are subsequently developed to increase specificity and thus reduced the side effects,
but have limitations such as the formation and development of drug resistance.
Resistance of therapeutic agents in an important problem in the treatment of cancer disease that is
believed to influence the effectiveness of targeted therapies and the prognosis of patients with cancer.
Although a patient initially was sensitive to some chemotherapeutic agents, he may also acquire cross-
resistance during treatment.
Several mechanism involve in anticancer resistance, including an increase in drugs efflux, alteration or
mutation of drug targets, drug detoxification and inactivation, impact on apoptosis, interference with
DNA replication and other ways.
Molecular Targeted Therapy in Anticancer
The cellular targets are genetically altered in cancer cells and are essential to tumour development and
survival.
Oncoprotein or oncogenes targets, which are mainly involved in various signalling pathways are
primarily products of gene fusions, obtained or functional mutations or overexpressed oncogenes.
Mechanisms of Anticancer Drug Resistance
Several mechanisms involved in resistance to anticancer drug, including an increase in drug efflux,
alteration or mutation of drug targets, drug detoxification and inactivation, impact on apoptosis,
interference with DNA replication and many other ways.
Expression of Drug Efflux Pumps
Multidrug resistance (MDR) occurred at the beginning of the treatment or during treatment when cells
resist to the treatment.
One of the mechanism was the increased expression of drug efflux pumps, such as P-glycoprotein (P-
gp) which is one of the ATP-binding cassette (ABC) transporters and was encoded by the MDR1
(ABCB1) gene.
P-gp become a target of several studies to identify novel compounds to counteract MDR.
, Alteration or Mutation of Drug Targets
Generally, the mutations of functional targets or some alterations of expression levels dramatically
influenced drug resistance.
New anticancer drugs that targeted oncogenic signalling pathways have been developed (cetuximab
and panitumumab).
The specific mutations in the EGFR gene of NSCLC are corelated with clinical responsiveness to the
TKI gefitinib. These mutations lead to the increase of growth factor signalling and susceptibility to the
inhibitor. Such mutations in NSCLC lead to the good response to cetuximab and panitumumab that
could bind to the extracellular domain of EGFR.
Drug Detoxification and Inactivation
Tumor resistance may be present at the beginning of treatment, develop during treatment, or become
apparent on re-treatment of the patient.
Clonal selection in this process was that cell lines produced highly resistant sub-clones on the low
concentrations of drugs exposure.
However, cells may be able to adapt by regulation of expression of resistance or target molecules
individually if they survived the initial exposure to the drug and did not require clonal selection.
This required changes in molecular levels such as epigenetic change and mutilation mechanisms.
Glutathione S-transferase was important for the development of drug resistance via direct
detoxification. It may decrease the concentration of anticancer drugs via the glutathione (GSH)-
conjugate export pump and special emphasis has been put on the function of GSTs in Phase II
detoxification.
Impact on Apoptosis
o The suppression of apoptosis is one mechanism by which tumour cells become drug resistant.
o Why cytotoxic drugs fail to kill sufficient tumour cells in the major human solid cancers, such as the
carcinomas, was suggested to be to the inherent inability of these cells to engage apoptosis after drug-
induced damage.
o Drug resistance mediated by anti-apoptosis is also a key MDR mechanism. B-cell
leukemia/lymohoma-2 (BCL-2) was one of the primary anti-apoptotic proteins.
o The BCL-2 family of proteins regulated cell fate by controlling the mitochondrial apoptotic pathway.
When activated, the pro-apoptotic members Bak and Bax could form high molecular weight oligomers
on the mitochondrial membrane potential and allowed the release of cytochrome to the cytoplasm and
consequently activating the caspases.
o JLP119 B lymphoma cells underwent apoptosis after the exposure to the topoisomerase II inhibitor
etoposide and this was dramatically reduced when the cells were cultured in the germinal centre
system.
Interference with DNA Replication
- On the stress of DNA damage of cancer cells by chemotherapeutic agents, cancer make changes in
some genes to produce the mutator phenotype.
- The obtaining of further mutations could repair DNA damage to make resistance to drug agents.
Irinotecan promoted cancer cell death by interfering with the topoisomerase type 1b enzyme (TOP1)
on DNA, generating cytotoxic protein-linked DNA breaks (PDBs).
- Topoisomerase-II was the primary target for various anticarcinogens. Through forming drug-Topo-II
complexes in cancer cells, these agents promoted DNA strand breaks and affected DNA replication.
Decreased sensitivity and activity of Topo-II were important in the development of drug resistance.
