Bettina Wick-Urban / Angiogenesis inhibitors discovered as anticancer drug.Vascular endothelial growth factor (VEGF) antagonists are now well established in the treatment of cancer and certain macular diseases of the eye.review.
Angiogenesis occurs in metabolically active tissues throughout life, from the womb to death (inset). The production of vascular endothelial growth factor (VEGF) is highly regulated in many physiological processes such as embryogenesis, the female menstrual cycle, pregnancy and wound healing, but alsoin diseases such as cancer, diabetic retinopathy, heart disease or stroke There is evidence that elevated VEGF concentrations also play a role in neurodegenerative diseases such as Alzheimer's disease.
Solid tumors depend on a network of capillaries that grow with them. Sizes of 2 mm2The supply of tissues with oxygen and nutrients is no longer guaranteed.The findings suggest that uncontrolled tumor growth is due not only to increased angiogenesis (the formation of new blood vessels), but also to genetic changes that reduce the release of inhibitors (1, 2).
Therapy: Tumor latency
Without the supply of new blood vessels, the tumor stops growing and remains asymptomatic.This so-called tumor latency can last from months to years.In this phase, depending on the model, angiogenesis inhibitors predominate or there is a balance.Therapeutic approaches Antiangiogenic agents aim to promote the latency of this tumor.
The primary drug target is VEGF: it is continuously secreted during tumor progression, although angiogenesis is stimulated by basic FGF or other growth factors such as TGFβ-1 (transforming growth factor β1).High levels of VEGF are associated with poor clinical outcomes. Patients have faster disease progression, shorter overall survival and higher recurrence rates (3, 4).
The approved VEGF antagonists are divided into three groups based on their point of attack (see diagram on page 34).
One group consists of recombinant antibodies such as bevacizumab, ranibizumab (an antibody fragment of bevacizumab that binds to VEGF), and ramucirumab.The first two drugs bind VEGF, preventing it from binding to the receptor, while ramucirumab, recently launched in Germany, binds to the VEGF receptor and blocks the VEGF binding site.
as blood vessels grow
Angiogenesis occurs in all rapidly growing or damaged tissues, stimulated by generalized hypoxia.New capillaries are formed, allowing oxygen and nutrients to reach all cells by diffusion.Parenchymal cells, such as those of the skin, heart, liver or brain, release the angiogenic factor VEGF-A (= VEGF), which stimulates the formation of new capillaries.Like placental growth factor (PGF) and VEGF-B a -E, VEGF belongs to a family of homodimeric glycoproteins that are structurally similar to platelet-derived growth factor (PDGF).
The main factor VEGF penetrates into neighboring blood vessels and binds with high affinity to VEGF receptors 1 and 2 (VEGFR-1 and -2) on endothelial cells.In addition, members of the VEGF family bind to the other three receptors with different affinities.Docking activates several intracellular growth signaling processes that stimulate the sprouting of new blood vessels, for example in the direction of the tumor. First, the connective tissue surrounding the capillaries dissolves; small protrusions of endothelial cells (apical cells) exposed to the highest concentrations of VEGF migrate into the tissue.Endothelial cells behind the apex cells proliferate and elongate the stolon.Subsequently, the tips of the two endothelial protrusions fuse to form new capillaries, which in the final step differentiate into arterioles or venules. Growth factors such as fibroblast growth factor (FGF), PDGF, and angiopoietin-1 recruit pericytes and promote the deposition of extracellular matrix, thus ensuring the final formationand stabilization of the capillary wall.
Angiogenesis is a finely regulated system.If the blood flows through the new capillaries and provides an adequate amount of oxygen to the surrounding tissues, the release of VEGF is inhibited.In addition, physiological inhibitors of angiogenesis, such as interferon-α, platelet factor 4 or angiostatin, are in homeostasis with angiogenic factors (1, 2).
The second group consists of receptor fusion proteins, so-called receptor traps, which intercept VEGF and prevent its binding to the receptor.Aflibercept consists of the VEGF-binding portion of the receptor ectodomains 1 and 2 of human VEGF and the Fc portion of human immunoglobulin IgG1.
Enzyme inhibitors are a third class of drugs that inhibit angiogenesis by inactivating intracellular VEGF receptor tyrosine kinases (TKIs).An example is axitinib, which binds with high affinity to three VEGF receptors and stops phosphorylation.In addition to VEGF receptor kinases, other TKIs bind with high affinity to other enzymes involved in angiogenesis, cell growth, and metastasis.In addition to VEGFR-1 to -3 tyrosine kinases, sunitinib also inactivates PDGF and c-kit (stem cell factor) receptor kinases, which also play a role in angiogenesis and inhibit cell growth and other important receptors and differentiation.In addition to several receptor tyrosine kinases, sorafenib inhibits several intracellular Raf kinases.These serine/threonine kinases transduce growth factor-mediated signals into the nucleus.Some of these receptors and enzymes can promote tumor development if they are overexpressed or mutated (proto-oncogenes).The multiple mechanisms required to suppress tumor growth promise to improve efficacy and reduce tumor resistance.
In addition to the multikinase inhibitors already mentioned, pazopanib, vandetanib, cabozantinib, and regorafenib are also approved for the treatment of various tumors.
as a first or second order combination
Angiogenesis inhibitors are used in combination with chemotherapy drugs to treat advanced or metastatic solid tumors.As shown with bevacizumab, they increase the effectiveness of the combination in several ways:
Existing tumor blood vessels recede and the tumor shrinks.Fewer blood vessels are formed and tumor growth is slowed down.In addition, bevacizumab normalized the permeability of surviving tumor vessels, implying a reduction in ascites formation or vascular fluid leakage (5) (Figure).
Angiogenesis inhibitors can be used as primary treatment for tumors (first line) or as second line treatment when initial treatment has not been successful and the tumor has progressed in growth.These drugs have not been tested in children and adolescents due to the emergence of indications in adulthood.Details of indications and dosages are summarized in Tables 1 and 2.
Bevacizumab: a first-line anticancer drug
Bevacizumab was the first VEGF inhibitor approved in Europe in 2005. In addition to first-line treatment for metastatic colon cancer (mCRC), humanized monoclonal antibodies are now also used in other metastatic tumors such as breast cancer (mBC) or renal cancer (mRCC).) or advanced tumors such as non-small cell carcinoma (NSCLC) or ovarian cancer (OC).
In clinical trials, the addition of bevacizumab to chemotherapy significantly extended the time to disease progression in all tumor types by 1.7 to 5.9 months.Bevacizumab achieved significantly longer overall survival only in cancer patients with metastatic colorectal cancer in combination with irinotecan/5-fluorouracil and leucovorin and in NSCLC patients receiving carboplatin/paclitaxel chemotherapy.Affected individuals live an average of 5 to 2 months longer.Bevacizumab also increased the proportion of patients who responded to 10% to 25%.When patients continued to receive bevacizumab after stopping chemotherapy, the time to progression of tumor growth increased by several months (6-10).
Treatment goal: improvement of vision.
Ranibizumab is used to treat neovascular (wet) age-related macular degeneration (AMD) and severe visual impairment (Table 1).They can be the result of macular edema due to diabetes, retinal vein occlusion or pathological myopia.
In AMD, VEGF levels in the eye are elevated, as is the case with edematous diseases.Increased concentrations of VEGF lead to excessive neovascularization of the choroid, the highly vascularized layer in the back of the eye between the cornea and retina.Blood and fluid leakage from the newly formed blood vessel due to increased permeability. Retinal thickening, edema, and subretinal or intraretinal hemorrhage, which can affect vision and vision and, if untreated, can cause blindness
Like the whole bevacizumab antibody, ranibizumab inhibited increased endothelial cell proliferation and decreased vascular permeability.Vision is preserved and vision has improved.
In clinical studies, ranibizumab delayed vision loss in approximately 95 percent of AMD patients, compared to 62 percent of patients who received a sham injection.Improvement of vision was observed in 34 percent and 5% from the first year of treatment.Patients who received early continuation treatment benefited the most from treatment.
Ranibizumab has shown similar superior efficacy compared to verticorin photodynamic therapy, which is approved for the treatment of AMD (11-15).with occlusive edema (approximately 30% treated with placebo) achieved a clinically significant improvement in vision within one year and continued improvement with Ranibizumab for macular edema (16-20).
Table 1: Overview of parenteral VEGF inhibitors
| DCI name, trade name | Molecular structure | Indications (selection) and approved doses | Route of administration, half-life (days) |
|---|---|---|---|
| bevacizumab, avastin® | recombinant humanized MAB | Metastatski CRC:5 or 10 mg/kg body weight every two weeks or 7.5 or 15 mg/kg body weight every three weeks in combination with fluoropyrimidine-based chemotherapy Metastatic breast cancer:10 mg/kg body weight every two weeks or 15 mg/kg body weight every three weeks with paclitaxel or capecitabine Advanced, metastatic or recurrent NSCLC:7.5 or 15 mg/kg every three weeks for 6 cycles of platinum-based chemotherapy Advanced and/or metastatic renal cell carcinoma:10 mg/kg of body weight every two weeks in combination with interferon alfa-2a Advanced epithelial ovarian, fallopian tube or primary peritoneal cancer:15 mg/kg body weight every three weeks in combination with carboplatin and paclitaxel | Intravenous infusion for the first 90 minutes, then 30 minutes Ho Chi Minh: |
| Early day Zuma b, etc. Bizma b® | A great fragment of humanized MAK. | Wet AMD, visual impairment due to BMD or macular edema due to VVR: 0.5 mg once monthly Visual impairment due to PM-induced CNV: 0.5 mg once | intravitreal injection HWZ: 9 |
| Ramucirumab, Cyramza® | recombinant humanized MAB | Advanced stomach cancer: 8 mg/kg every two weeks | intravenous injection HWZ: 8 |
| Confirm, Elias®, Zaltrap® | Extracellular fragment of human VEGF receptor and fusion protein of human Fc fragment IgG1 | wet AMD:2 mg per month, then 3 injections every 2 months Macular edema caused by ZVV:2mg per month DMMO:2 mg per month after five injections every two months Metastatski CRC:4 mg/kg of body weight in combination with irinotecan, 5-fluorouracil and folic acid | Ophthalmology: intravitreal injections Tumor indications: intravenous infusion over 60 minutes. HWZ: 6 |
Ranibizumab i bevacizumab
Although ranibizumab is approved for the treatment of AMD, bevacizumab, which has the same antigenic specificity, is not approved for the treatment of AMD.However, since bevacizumab is much cheaper, it is used by ophthalmologists.For a long time there have been no controlled comparative studies.
Several manufacturer-independent studies lasting up to two years and published in 2012 and 2013 found the two drugs to be equally effective and tolerable.Both monthly dosing and on-demand treatment as the disease progressed resulted in clinically significant improvements in vision.The number of deaths and the incidence of serious adverse events were comparable.A new systematic review by the independent Cochrane Collaboration assessed side effects in nine comparative studies involving nearly 4,000 patients and found no difference in the effect rates of serious side effects and death.The only difference: intravitreal bevacizumab was associated with more gastrointestinal side effects (21-24).
Another antibody, ramucirumab, has been available for several days in Germany.In April 2014, the US FDA approved it for advanced stomach cancer.In clinical trials, ramucirumab significantly improved survival compared to placebo in patients whose disease had progressed after treatment with platinum or a fluoropyrimidine (5.2 months versus 3.8 months). The active substance is currently being tested in new studies in advanced or metastaticcolon, lung, breast, liver and uterine cancer (25, 26).
Table 2: Overview of approved orally bioavailable tyrosine kinase inhibitors
| INN, product name | Indications and approved doses | pharmaceutical form, half-life |
|---|---|---|
| Inn Hibi Tori Chiro Man Machine Why | ||
| Axitinib, Inlida® | Advanced renal cell carcinoma after failure of treatment with sunitinib or cytokines:5 mg twice a day | the pill HWZ: 2.5 to 6.1 hours |
| Cabozantinib, Comtriq® | Inoperable advanced or metastatic medullary thyroid cancer:140 mg once a day | haircut HWZ: 120 hours |
| Sunitinib, Sutent® | Inoperable metastatic gastrointestinal stromal tumor; advanced or metastatic renal cell carcinoma:Treatment cycle: 50 mg once daily for 4 weeks with a 2-week rest period Inoperable or metastatic pNET: 37.5 mg qd with no rest period | haircut Half-life: 40 to 60 hours (80 to 110 hours for the active metabolite) |
| Pazopanib, Watling® | advanced CCR; advanced soft tissue sarcoma:800 mg once a day | the pill HWZ: 30.9 hours |
| Van de Tani, Capresa® | Inoperable advanced or metastatic medullary thyroid cancer:300 mg once a day | the pill HWZ: 19 roofs |
| Serine/threonine-tyrosine kinase - Hammer | ||
| Nehwar Sorafiniv® | Liver cancer; advanced renal cell carcinoma after failure of cytokine therapy; differentiated, progressive, locally advanced or metastatic thyroid cancer, resistant to radioactive iodine:400 mg twice a day | the pill HWZ: 25 to 48 hours |
| Regorafenib, Regorafenib® | Metastatic colorectal carcinoma, unresectable/metastatic gastrointestinal stromal tumor:Treatment cycle: 160 mg once a day for three weeks with a one week break | the pill HWZ: 20 to 30 hours |
Aflibercept as receptor decoy
Aflibercept, like ranibizumab, is approved for the treatment of visual impairment due to AMD and macular edema as an intravitreal injection (Table 1).In clinical trials, aflibercept was as effective as ranibizumab.Both drugs preserved and improved vision in patients with AMD during a two-year study (27).
Aflibercept also significantly improved vision in patients with edema and reduced retinal thickness compared with sham injections or laser photocoagulation over the two-year study period.There are no direct comparison studies with ranibizumab (28-30).
The intravenous solution is approved in combination with irinotecan/5-fluorouracil/leucovorin (FOLFIRI) as second-line therapy in patients with metastatic colon cancer who have progressed despite oxaliplatin. In clinical studies, the addition of aflibercept to FOLFIRI significantly prolonged overall survival ( 13,5 months versus 12.1 months) and progression-free survival (6.9 months versus 4.7 months) compared to placebo. This was true even for patients who had previously received bevacizumab. (31) There are nostudies comparing bevacizumab and FOLFIRI.
Aflibercept is also currently being evaluated clinically in advanced or metastatic cancers of the colon, lung, thyroid, or uterus (31).
inhibitor multikinaze
Axitinib is approved for the treatment of patients with advanced RCC who have failed treatment with sunitinib or cytokines (Table 2).Disease progression in patients taking axitinib tablets was significantly later than in the control group.who took sorafenib tablets.Patients previously treated with interleukin 2 or interferon alpha benefited the most: progression-free survival almost doubled with axitinib compared with sorafenib (12.0 months vs. 6.6 months).The difference was significant but small (4.8 months vs. 3.4 months) if the patients were previously treated with sunitinib. The effect on overall survival was comparable (32, 33). In patients with metastatic renal cell carcinoma who were not treated,these two drugs significantly prolong the time to tumor progression (34).
Sorafenib is approved for the treatment of advanced liver cancer.In clinical trials, the substance prolonged overall survival and progression-free survival by three months compared to placebo.As adjuvant therapy for advanced renal cell carcinoma, sorafenib also prolongs overall survival and delays the time Patients with advanced or metastatic thyroid cancer experienced increased progression-free survival, but not overall survival, compared with placebo (35-37).
Sunitinib is indicated for the treatment of gastrointestinal stromal tumors (GIST), pancreatic neuroendocrine tumors, or advanced or metastatic renal cell carcinoma.Patients with GIST benefit from increased progression-free survival (38-41).People with pancreatic tumors and renal cell carcinoma also had longer overall survival (compared to placebo or alpha interferon).
Studies have shown that pazopanib prolongs progression-free survival, but not overall survival, in patients with advanced renal cell carcinoma or soft tissue sarcoma.In a direct comparison with sunitinib, both showed similar efficacy in CRC, but pazopanib appeared to cause fewer side effects such as fatigue, hand-foot syndrome, or thrombocytopenia (42-44).
Regorafenib is the only multikinase inhibitor to date that has been able to significantly prolong survival in patients with previously treated metastatic colorectal cancer (6.4 months placebo versus 5.0 months placebo).The drug is also effective in patients with GIST who do not respond to imatinib or sunitinib (45, 46).
Vandetanib and cabozantinib are used to treat rare, advanced, or metastatic medullary thyroid cancer.Their progression-free survival was approximately 11 and 7 months longer than placebo (47, 48).
list of abbreviations
AMD semiconductors:age-related neovascular macular degeneration
Number:Choroidal neovascularization
DMMO:diabetic macular edema
Fiber growth factor:fibroblast growth factor
Essence:Gastrointestinal stromal tumor
Metastatic colorectal cancer:metastatic colon cancer
mobile BC:metastatic breast cancer
Metastatic renal cell carcinoma:metastatic kidney cancer
Non-small cell lung cancer:non-small cell lung cancer
overclocking:ovarian cancer
Platelet Growth Factor:platelet growth factor
Prostaglandins:placental growth factor
afternoon:pathological myopia
Red:Pancreatic neuroendocrine tumors
pressure:reversible posterior encephalopathy syndrome
Right ventricular volume:retinal vein occlusion
Beta-1 transforming growth factor:transforming growth factor beta 1
In cracking Chirojin why:Inn Hibi Tori Chiro Man Machine Why
Vascular endothelial growth factor (R):Vascular endothelial growth factor (receptor)
similar side effects
All drug groups have very similar side effects.High blood pressure, fatigue, weakness, diarrhea, abdominal pain, and proteinuria are common and usually not serious.The higher the dose, the higher the incidence of hypertension and proteinuria appears to be.High blood pressure is usually well controlled with antihypertensive drugs.
Bleeding, gastrointestinal perforation, fistula, neutropenia and infection are serious side effects of treatment.In addition, patients are at increased risk of arterial thromboembolism, such as stroke, heart attack, or transient ischemic attack.Venous thromboembolism in the lungs and in the deep veins of the legs. Impaired wound healing occurs due to inhibition of VEGF, for example, after surgery. In addition, these drugs reduce the ejection capacity of the left ventricle and cause congestive heart failure (49).
PRES syndrome
Isolated cases of posterior reversible encephalopathy syndrome (PRES) have been reported in clinical trials or in post-marketing experience for all drug groups.PRES is a neurological disorder characterized by headache, seizures, drowsiness, confusion, blindness, high blood pressure, etc., and can lead to death.Patients should inform their doctor immediately if they notice such signs.If the MRI confirms this diagnosis, the drug should be stopped immediately.
Unlike kinase inhibitors, antibodies and aflibercept can cause hypersensitivity reactions, including anaphylaxis, due to their protein properties.
The problem of tumor drug resistance
Problems with neoplastic diseases: Resistance to the used cytostatics often occurs, that is, the tumor stops responding to treatment after a certain time and reappears.Mutations, DNA repair systems and increased expression of efflux pumps play a role.When bevacizumab was introduced, it was expected to prevent tumor resistance because the tumor cells were not directly inhibited.However, this did not materialize.Multikinase inhibitors are also expected to outcompete tumor cells.However, resistance to these agents also exists (49).
cardiac effects
Cardiac side effects are specific to kinase inhibitors.They may prolong the QT interval, especially in patients with a history of cardiac arrhythmias, thereby increasing the risk of ventricular arrhythmias, including torsades de pointes.Kinase inhibitors are toxic to the liver and may cause liver failure. Closely monitor transaminase and bilirubin levels; if levels are high, dose should be reduced or drug should be withheld until levels return to normal. Hypothyroidism has also been observed with some kinase inhibitors.
Patients usually suffer from hand-foot syndrome, which is erythematous skin changes on the palms and soles with pain, swelling, and redness.Serious skin reactions, including Stevens-Johnson syndrome and epidermal necrolysis, have been observed.toxic, with sunitinib, regorafenib, or vandetanib Osteonecrosis of the jaw occurred when intravenous bisphosphonates were coadministered with sunitinib or cabozantinib (49).
Local side effects in the eye.
The side effects of the intravitreal drugs ranibizumab and aflibercept are similar and primarily affect the eye.Patients often complain of eye irritation after the injection, such as pain, dryness, itching or increased tear flow.Hyperemia of the eye, increased intraocular pressure, bleeding, vitreous ablation or visual disturbances.Serious side effects, such as infection inside the eye (endophthalmitis), can lead to blindness, retinal detachment, retinal tears, or traumatic cataracts, but are less common (49).
Simultaneous use of strong CYP3A4 inhibitors (eg ketoconazole) or inducers (eg phenytoin), with the exception of sorafenib, is not recommended during therapy with kinase inhibitors. Either the dose should be adjusted due to increased or decreased plasma concentrations.
New targets: psoriasis, obesity and diabetes
In the skin, VEGF is secreted primarily by keratinocytes.VEGF levels are elevated in affected skin areas, as well as in healthy areas and in the plasma of patients with psoriasis.Tumor necrosis factor alpha (TNF-α), also elevated in psoriasis, also stimulates angiogenesis. In patients with elevated plasma VEGF levels, psoriasis begins before the age of 40 and is often associated with psoriatic arthritis. Inhibition of the novel dual decoy receptor simultaneously withVEGF-A and TNF-α (Valpha) and approved aflibercept reduces skin symptoms such as epidermal thickness and increases vascular distribution in a normalized mouse model of psoriasis (50, 51).
The findings suggest that angiogenesis inhibitors may block the delivery of nutrients to abdominal adipose tissue.In the first study in overweight patients, evening primrose leaf extract (ALS-L1023) reduced body weight by 15% after 12 weeks compared to baseline.The extract, taken in tablet form, inhibits angiogenic growth factors and metalloproteinases in vitro.A larger study in Korea is currently examining efficacy and tolerability (52, 53).
Diabetics may also benefit from angiogenesis inhibition in the future.In animal studies, aflibercept lowered blood sugar levels.As a possible mechanism of action, researchers suspect that aflibercept causes blood vessel degeneration, increasing the number of liver cells that are starved of oxygen.Under hypoxic conditions, the protein HIF-2α is released, which stimulates the formation of insulin receptor substrate 2 (IRS2).IRS2 activates insulin receptors, cells respond more strongly to insulin and cells absorb more glucose from the blood.Blood sugar drops.This newly discovered mechanism of action may have beneficial effects on the metabolic profile of type 1 and type 2 diabetes. Clinical trials show to what extent this also applies to humans (54)./
author's literary work
Author
Bettina Wick-UrbanShe studied pharmacy at the Albert Ludwig University in Freiburg.In 1996, she completed her PhD in Experimental Cancer Therapy in Basel and Freiburg and worked as a consultant at the ABDA Drug Information Center until 1998. She then moved to the pharmaceutical industry and worked in a research clinic from 1999 to 2004, including two years in the United StatesThe author has worked in various positions in the field of medical and scientific informatics since 2004. In mid-2006, he completed his studies in journalism.
Dra.Bettina Wick-Urban
email:wickurban@web.de
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