Limits...
Nonsmall cell lung cancer therapy: insight into multitargeted small-molecule growth factor receptor inhibitors.

Roy M, Luo YH, Ye M, Liu J - Biomed Res Int (2013)

Bottom Line: To date, lung cancer is the leading cause of cancer-related death worldwide, among which nonsmall cell lung cancer (NSCLC) comprises about 85%.Taking into account the side effects of surgery, radiation, platinum-based doublet chemotherapy, and the growth self-sufficiency characteristic of cancer cells, drugs have been discovered toward growth factor receptor (GFR) to treat NSCLC.As expected, these drugs provide a greater benefit.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology Research Center, School of Life Science and State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan 410078, China.

ABSTRACT
To date, lung cancer is the leading cause of cancer-related death worldwide, among which nonsmall cell lung cancer (NSCLC) comprises about 85%. Taking into account the side effects of surgery, radiation, platinum-based doublet chemotherapy, and the growth self-sufficiency characteristic of cancer cells, drugs have been discovered toward growth factor receptor (GFR) to treat NSCLC. As expected, these drugs provide a greater benefit. To increase the efficacy of such growth factor receptor tyrosine kinase inhibitors (RTKIs), coinhibition of GFR signaling pathways and combination of inhibitors along with radiation or chemotherapy have drew intense insight. Although clinical trials about single-agent RTKIs or their combination strategies suggest their increase potency against cancer, they are not beyond adverse effects, and sometimes the effects are more deadly than chemotherapy. Nevertheless the hope for RTKIs may be proved true by further researches and digging deep into cancer therapeutics.

Show MeSH

Related in: MedlinePlus

Growth factor receptor inhibition. (a) Immuno-modulatory mechanism for monoclonal antibodies. Binding of monoclonal antibodies (mAbs) to a specific target on a tumour cell can cause either complement-dependent cytotoxicity (CDC) by the interaction of C1q complement factor with the CH2 constant region of the mAb, which leads to the activation of complement classical pathway and induces the formation of a membrane-attack complex (MAC) for the lysis of tumour cells or antibody-dependent cellular cytotoxicity (ADCC) by the interaction of CH3 region of the mAbs with FcγRIIIa expressed by effector cells (macrophages or NK cells) which leads to phagocytosis by macrophages or undergo cytolysis by NK cells. C3b, which is generated during CDC, can facilitate phagocytosis and cytolysis through its interaction with macrophage or natural killer (NK) cell. This effect is termed as complement-dependent cell-mediated cytotoxicity (CDCC). (b) Small-molecule receptor tyrosine kinase inhibitor interaction to its specific site. Small-molecule tyrosine kinase inhibitors (TKIs) function as ATP analogues to compete with ATP for their binding site and block the receptor mediated downstream signaling.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3713357&req=5

fig2: Growth factor receptor inhibition. (a) Immuno-modulatory mechanism for monoclonal antibodies. Binding of monoclonal antibodies (mAbs) to a specific target on a tumour cell can cause either complement-dependent cytotoxicity (CDC) by the interaction of C1q complement factor with the CH2 constant region of the mAb, which leads to the activation of complement classical pathway and induces the formation of a membrane-attack complex (MAC) for the lysis of tumour cells or antibody-dependent cellular cytotoxicity (ADCC) by the interaction of CH3 region of the mAbs with FcγRIIIa expressed by effector cells (macrophages or NK cells) which leads to phagocytosis by macrophages or undergo cytolysis by NK cells. C3b, which is generated during CDC, can facilitate phagocytosis and cytolysis through its interaction with macrophage or natural killer (NK) cell. This effect is termed as complement-dependent cell-mediated cytotoxicity (CDCC). (b) Small-molecule receptor tyrosine kinase inhibitor interaction to its specific site. Small-molecule tyrosine kinase inhibitors (TKIs) function as ATP analogues to compete with ATP for their binding site and block the receptor mediated downstream signaling.

Mentions: In the early 1980s mAb was first applied for cancer treatment, about 10 years earlier than the development of small-molecule TKIs. Although early clinical trials with murine mAbs failed owing to their short half-life and limited activity, genetic engineering has made it possible to design chimeric mouse-human mAbs and humanized mAbs [28]. Among a number of these antibodies (Table 1), bevacizumab, a humanized mAb to vascular endothelial growth factor (VEGF), is currently approved for use in combination with chemotherapy in multiple countries for the treatment of patients with metastatic NSCLC [29]. The mAbs can confer their antitumor activity by two putative mechanisms. For the direct action, it can block the function of target signaling molecules resulting in inhibition of cell-cycle progression, regression of angiogenesis, induction of apoptosis, and internalization of receptors or it can be conjugated with toxins, cytokines, and even with small-molecule agents [28, 30]. The second or indirect mechanism of mAb is mediated by the immune system through complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated cytotoxicity (CDCC), or antibody-dependent cellular cytotoxicity (ADCC) [31] (Figure 2(a)).


Nonsmall cell lung cancer therapy: insight into multitargeted small-molecule growth factor receptor inhibitors.

Roy M, Luo YH, Ye M, Liu J - Biomed Res Int (2013)

Growth factor receptor inhibition. (a) Immuno-modulatory mechanism for monoclonal antibodies. Binding of monoclonal antibodies (mAbs) to a specific target on a tumour cell can cause either complement-dependent cytotoxicity (CDC) by the interaction of C1q complement factor with the CH2 constant region of the mAb, which leads to the activation of complement classical pathway and induces the formation of a membrane-attack complex (MAC) for the lysis of tumour cells or antibody-dependent cellular cytotoxicity (ADCC) by the interaction of CH3 region of the mAbs with FcγRIIIa expressed by effector cells (macrophages or NK cells) which leads to phagocytosis by macrophages or undergo cytolysis by NK cells. C3b, which is generated during CDC, can facilitate phagocytosis and cytolysis through its interaction with macrophage or natural killer (NK) cell. This effect is termed as complement-dependent cell-mediated cytotoxicity (CDCC). (b) Small-molecule receptor tyrosine kinase inhibitor interaction to its specific site. Small-molecule tyrosine kinase inhibitors (TKIs) function as ATP analogues to compete with ATP for their binding site and block the receptor mediated downstream signaling.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713357&req=5

fig2: Growth factor receptor inhibition. (a) Immuno-modulatory mechanism for monoclonal antibodies. Binding of monoclonal antibodies (mAbs) to a specific target on a tumour cell can cause either complement-dependent cytotoxicity (CDC) by the interaction of C1q complement factor with the CH2 constant region of the mAb, which leads to the activation of complement classical pathway and induces the formation of a membrane-attack complex (MAC) for the lysis of tumour cells or antibody-dependent cellular cytotoxicity (ADCC) by the interaction of CH3 region of the mAbs with FcγRIIIa expressed by effector cells (macrophages or NK cells) which leads to phagocytosis by macrophages or undergo cytolysis by NK cells. C3b, which is generated during CDC, can facilitate phagocytosis and cytolysis through its interaction with macrophage or natural killer (NK) cell. This effect is termed as complement-dependent cell-mediated cytotoxicity (CDCC). (b) Small-molecule receptor tyrosine kinase inhibitor interaction to its specific site. Small-molecule tyrosine kinase inhibitors (TKIs) function as ATP analogues to compete with ATP for their binding site and block the receptor mediated downstream signaling.
Mentions: In the early 1980s mAb was first applied for cancer treatment, about 10 years earlier than the development of small-molecule TKIs. Although early clinical trials with murine mAbs failed owing to their short half-life and limited activity, genetic engineering has made it possible to design chimeric mouse-human mAbs and humanized mAbs [28]. Among a number of these antibodies (Table 1), bevacizumab, a humanized mAb to vascular endothelial growth factor (VEGF), is currently approved for use in combination with chemotherapy in multiple countries for the treatment of patients with metastatic NSCLC [29]. The mAbs can confer their antitumor activity by two putative mechanisms. For the direct action, it can block the function of target signaling molecules resulting in inhibition of cell-cycle progression, regression of angiogenesis, induction of apoptosis, and internalization of receptors or it can be conjugated with toxins, cytokines, and even with small-molecule agents [28, 30]. The second or indirect mechanism of mAb is mediated by the immune system through complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated cytotoxicity (CDCC), or antibody-dependent cellular cytotoxicity (ADCC) [31] (Figure 2(a)).

Bottom Line: To date, lung cancer is the leading cause of cancer-related death worldwide, among which nonsmall cell lung cancer (NSCLC) comprises about 85%.Taking into account the side effects of surgery, radiation, platinum-based doublet chemotherapy, and the growth self-sufficiency characteristic of cancer cells, drugs have been discovered toward growth factor receptor (GFR) to treat NSCLC.As expected, these drugs provide a greater benefit.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology Research Center, School of Life Science and State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan 410078, China.

ABSTRACT
To date, lung cancer is the leading cause of cancer-related death worldwide, among which nonsmall cell lung cancer (NSCLC) comprises about 85%. Taking into account the side effects of surgery, radiation, platinum-based doublet chemotherapy, and the growth self-sufficiency characteristic of cancer cells, drugs have been discovered toward growth factor receptor (GFR) to treat NSCLC. As expected, these drugs provide a greater benefit. To increase the efficacy of such growth factor receptor tyrosine kinase inhibitors (RTKIs), coinhibition of GFR signaling pathways and combination of inhibitors along with radiation or chemotherapy have drew intense insight. Although clinical trials about single-agent RTKIs or their combination strategies suggest their increase potency against cancer, they are not beyond adverse effects, and sometimes the effects are more deadly than chemotherapy. Nevertheless the hope for RTKIs may be proved true by further researches and digging deep into cancer therapeutics.

Show MeSH
Related in: MedlinePlus