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*It is only for medical professionals to read the reference article for an overview of the development history and research progress of platinum drugs! Platinum-based drugs were developed in the 1960s.
Since the first generation of platinum-based anti-tumor drug cisplatin was approved in the United States in 1978, the research and development of new platinum-based drugs has experienced nearly 40 years of development.
Platinum drugs are widely used in the treatment of common malignant tumors such as lung cancer, bladder cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, colorectal cancer and head and neck cancer due to their unique anti-cancer mechanism and broad anti-cancer spectrum.
.
With the advancement of medical research, the mechanism of action of platinum drugs has been discovered in more in-depth studies.
In the near future, research on potential curative effects and drug resistance related mechanisms, side effects protection and immunomodulation is expected to be further applied in clinical practice.
What are the major types of platinum drugs? What is the history of the discovery and application of platinum drugs? What are the mechanisms of action? What are the new developments in current research and development? We will introduce them separately below.
The past and present of the platinum-based drug family ■ The first-generation platinum-based cisplatin is also known as cisplatin.
Italian chemist Michele Peyrone first reported the synthesis of cisplatin in 1844, but the biological activity of cisplatin was first confirmed in 1965.
Soon, the anti-tumor effect of cisplatin was confirmed, and the US FDA approved cisplatin for the treatment of testicular cancer in 1978.
Subsequently, the scope of application of cisplatin continued to expand, and it was widely used clinically as a first-line treatment for lung cancer, ovarian cancer, head and neck cancer, gastric cancer and other tumors.
Platinum compounds have subsequently become the main components of other types of cancer chemotherapy regimens, and platinum preparations have become a milestone in the development of cancer treatments.
The advantages of cisplatin are: high anti-cancer activity, low cross-resistance, and the use of combination drugs.
However, cisplatin is more nephrotoxic and prone to nausea and vomiting.
The appearance of Ondansetron alleviates the nausea and vomiting caused by cisplatin, and strengthens the position of cisplatin in cancer chemotherapy.
Figure 1 The chemical structure of cisplatin ■ The second-generation platinum-based carboplatin was developed in the 1980s and went on the market in the United States in 1986.
In the structure, cyclobutane dicarboxylic acid was used to replace the two chloride ions on the cisplatin molecule to increase the compound Its water solubility is 16 times that of cisplatin, and it has cross-resistance with cisplatin.
The advantages of carboplatin are: in addition to the toxicity of the hematopoietic system, other side effects are lower than that of cisplatin, and the efficacy is similar to that of cisplatin.
Therefore, it was quickly recognized by the market in Western developed countries.
Figure 2 The chemical structure of carboplatin.
Nidaplatin was first approved for marketing in Japan in June 1995.
Nidaplatin is more effective than cisplatin for head and neck tumors and esophageal cancer.
Nedaplatin uses glycolic acid to replace the two chloride ions on the cisplatin molecule.
The solubility in water is about 10 times that of cisplatin, and it changes the distribution of the drug in the kidneys.
Its nephrotoxicity and gastrointestinal side effects are relatively high.
Cisplatin has been reduced.
Its dose-limiting toxicity is thrombocytopenia caused by bone marrow suppression, and nedaplatin is still effective in patients who are resistant to cisplatin.
Figure 3 The chemical structure of Nidaplatin ■ The third-generation platinum oxaliplatin was approved by the US FDA in 2002.
Oxaliplatin maintains the cis-structure of cisplatin and introduces a hydrophobic diaminocyclohexane ligand to prevent the binding of repair proteins to DNA.
Therefore, oxaliplatin becomes the first platinum resistant to drug resistance in tumor cells.
Class of drugs.
Oxaliplatin is more toxic to the gastrointestinal tract, liver, kidney and bone marrow than cisplatin and carboplatin, and it is well tolerated.
Oxaliplatin is the first platinum drug with a significant effect on colon cancer.
It is often used clinically in combination with 5-fluorouracil or capecitabine and calcium leucovorin.
In addition, oxaliplatin also has a good effect on non-small cell lung cancer, gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, malignant lymphoma, esophageal cancer, liver cancer and head and neck tumors.
Figure 4 The chemical structure of oxaliplatin Table 1 How are platinum drugs compared to platinum drugs to fight cancer? Platinum anticancer drugs are cell cycle non-specific drugs.
In the early studies of platinum drugs, DNA was determined to be the main one Cell target.
The three platinum drugs that are currently popular in cancer treatment-cisplatin, carboplatin and oxaliplatin, all impair normal DNA function by producing monoadducts and DNA crosslinks.
They are generally considered to be close to alkylating agents.
Its electrophilicity leads to reaction with nucleophilic residues of DNA molecules, thereby mediating tumor cell necrosis or apoptosis.
Many cancers have defective DNA repair, a feature that also leads to secondary drug resistance.
Resistance mechanism is one of the main research areas of platinum compounds.
Drug accumulation, drug efflux, factors that prevent the drug from interacting with its target, ways to eliminate target damage, and factors and pathways involved in cell response to injury have been widely discussed in preclinical models.
In addition, the genome-wide functional screening method has revealed new discoveries in the absorption of platinum-based drugs.
About half of cisplatin and carboplatin can enter cells through the widely expressed volume-regulated negative ion channel (VRAC).
Therefore, this heterogeneous channel may be a useful biomarker.
In addition, platinum-based treatments may be improved in the future by optimizing the combination of immunotherapy, side effects management, and the use of nano-delivery devices.
In the next few years, platinum drugs may remain the cornerstone of cancer treatment standards.
Figure 5 The mechanism of action of platinum-based drugs The differences in the DNA damage response (DDR) of the newly developed multiple platinum-based preparations provide a useful explanation for drug sensitivity.
Most cancers have lost a key DDR pathway during evolution.
Therefore, tumor cells that lack proper DNA repair will die.
The normal cells of the body can still cope with this damage.
For example: DNA cross-linking caused by platinum drugs.
Among the different DDR mechanisms, the homologous recombination (HR) pathway is of particular interest because it mediates the error-free repair of cytotoxic double-strand breaks.
Because HR-deficient tumors are highly sensitive to DNA cross-linking agents, high-dose carboplatin-based chemotherapy can cure BRCA1 or BRCA2-related metastatic breast cancer.
Such an intensive treatment plan is suitable for young people and people with strong physique, but it is also controversial.
The new generation of platinum compounds may have fewer side effects and have sufficient DNA cross-linking activity to kill HR-deficient tumors.
Figure 6 Platinum compounds and their preparations.
Platinum drugs developed based on the mechanism of action are different from existing clinical drugs: including multinuclear platinum agents, monofunctional derivative preparations and platinum (IV) prodrugs.
There are many differences between these platinum preparations and traditional platinum preparations.
Multinuclear platinum agents, such as triplatin, have a unique long-acting mechanism of coordination and electrostatic interaction with molecules to generate phosphate clamps, a ring structure.
Another way to further optimize is to improve drug delivery.
Use nano delivery particles and nano formulations or tumor targeting polymers.
Liposomal cisplatin formulations, such as lipoplatin: Encapsulation of platinum-based agents into liposomes can increase bioavailability and reduce toxicity.
Other preclinical research methods aim to improve the release efficiency, release profile and storage stability of tumor tissue-targeted liposome capsules.
For example, in rats with bladder cancer, the structure of polyethylene glycol liposomes increases the exposure time of the tumor to the drug and reduces the toxicity.
Where does the platinum family go in the future? The discovery of new mechanisms of sensitivity or resistance to platinum compounds provides valuable information for drug development and can be further applied to the clinic.
Platinum compounds are quite ancient drugs, and it is unreasonable to conclude prematurely.
However, new preclinical and clinical observations, especially with regard to potential therapeutic effects and clinically relevant mechanisms of drug resistance, protection of side effects and immunomodulatory effects are ongoing.
Further studies on the interaction of platinum drugs with biomolecules other than DNA may reveal new mechanisms.
A new preclinical model has been established, which can be used to protect patients from the side effects caused by cisplatin.
Research linking the efficacy of chemotherapy (including platinum-based therapies) to microbes provides a new window for future development.
Evidence shows that bacteria control the response to treatment by regulating the microenvironment.
The definition of the active molecular characteristics of platinum compounds and the characteristics of patients with expected benefits, including understanding of concomitant treatments (antibiotics and effects on the microbiota, glucocorticoids, etc.
) will help optimize platinum-based anti-tumor treatments.
References: [1]Rottenberg Sven, Disler Carmen, Perego Paola.
The rediscovery of platinum-based cancer therapy.
[J].
Nature reviews.
Cancer,2021,21(1).
[2]Kelland, L.
The resurgence of platinum-based cancer chemotherapy.
Nat.
Rev.
Cancer 7, 573–584 (2007).
[3]Lippard, SJ New chemistry of an old molecule: cis-[Pt(NH3)2Cl2.
Science 218, 1075–1082 (1982 )[4]Wang Yujing,Xiong Huijuan,Wu Shasha,Zhou Xuewen,Wang Xiaobo.
The research status and progress of platinum anticancer drugs[J].
Journal of Hubei University of Science and Technology (Medical Edition),2020,34(03):270-273.
[5]Sun Piao, Ding Yang, Zhou Jianping.
Research progress of platinum anti-tumor drug nano-delivery system[J].
Chinese Journal of Pharmaceutical Industry, 2019, 50(12): 1383-1392.
Expert profile Liu Jinglin, Tianjin Medical University Tumor Introduction to the Department of Pharmacists in the Department of Pharmacy of the Hospital There are 82 people in the Department of Pharmacy of Tianjin Cancer Hospital, who are responsible for the supply and adjustment of clinical and scientific research drugs, as well as clinical pharmacy services and pharmacy management. Under the Department of Pharmacy, there are Chinese and Western pharmacies, inpatient pharmacies, intravenous fluid distribution centers, daytime dispensing, clinical pharmacy and other departments, equipped with outpatient automatic medicine dispensers, granule automatic dispensing machines, inpatient automatic oral medicine dispensers, and intravenous liquid dispensing Automatic equipment such as automatic sorter has a complete and scientific hardware management system.
We pass pre-prescription review; prescription and doctor's advice review work; through clinical pharmacists participating in the management of drug treatment in clinical departments to ensure the safe and reasonable medication.
In addition, the pharmacy research work should be carried out in accordance with the actual needs of clinical practice, and gradually form the characteristics of hospital pharmacy that combines clinical and scientific research.
Through the continuous improvement of the hardware and software system, pharmacy as a discipline is gradually developing towards precision and refinement.
Hospital pharmacy provides patients with all-round, full-chain pharmacy services, and escorts the realization of reasonable, safe and effective medication.
Wonderful review of past issues ☑ Do you know that these medicines cannot be used together? ☑ What should I pay attention to when treating NSCLC with ALK-TKI? One article to understand! ☑ Wonderful! If Cao Cao had a brain tumor with unbearable pain, what would Hua Tuo do? ☑ How to arrange diet and daily life for targeted and immunotherapy patients? Super full guide is here
Since the first generation of platinum-based anti-tumor drug cisplatin was approved in the United States in 1978, the research and development of new platinum-based drugs has experienced nearly 40 years of development.
Platinum drugs are widely used in the treatment of common malignant tumors such as lung cancer, bladder cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, colorectal cancer and head and neck cancer due to their unique anti-cancer mechanism and broad anti-cancer spectrum.
.
With the advancement of medical research, the mechanism of action of platinum drugs has been discovered in more in-depth studies.
In the near future, research on potential curative effects and drug resistance related mechanisms, side effects protection and immunomodulation is expected to be further applied in clinical practice.
What are the major types of platinum drugs? What is the history of the discovery and application of platinum drugs? What are the mechanisms of action? What are the new developments in current research and development? We will introduce them separately below.
The past and present of the platinum-based drug family ■ The first-generation platinum-based cisplatin is also known as cisplatin.
Italian chemist Michele Peyrone first reported the synthesis of cisplatin in 1844, but the biological activity of cisplatin was first confirmed in 1965.
Soon, the anti-tumor effect of cisplatin was confirmed, and the US FDA approved cisplatin for the treatment of testicular cancer in 1978.
Subsequently, the scope of application of cisplatin continued to expand, and it was widely used clinically as a first-line treatment for lung cancer, ovarian cancer, head and neck cancer, gastric cancer and other tumors.
Platinum compounds have subsequently become the main components of other types of cancer chemotherapy regimens, and platinum preparations have become a milestone in the development of cancer treatments.
The advantages of cisplatin are: high anti-cancer activity, low cross-resistance, and the use of combination drugs.
However, cisplatin is more nephrotoxic and prone to nausea and vomiting.
The appearance of Ondansetron alleviates the nausea and vomiting caused by cisplatin, and strengthens the position of cisplatin in cancer chemotherapy.
Figure 1 The chemical structure of cisplatin ■ The second-generation platinum-based carboplatin was developed in the 1980s and went on the market in the United States in 1986.
In the structure, cyclobutane dicarboxylic acid was used to replace the two chloride ions on the cisplatin molecule to increase the compound Its water solubility is 16 times that of cisplatin, and it has cross-resistance with cisplatin.
The advantages of carboplatin are: in addition to the toxicity of the hematopoietic system, other side effects are lower than that of cisplatin, and the efficacy is similar to that of cisplatin.
Therefore, it was quickly recognized by the market in Western developed countries.
Figure 2 The chemical structure of carboplatin.
Nidaplatin was first approved for marketing in Japan in June 1995.
Nidaplatin is more effective than cisplatin for head and neck tumors and esophageal cancer.
Nedaplatin uses glycolic acid to replace the two chloride ions on the cisplatin molecule.
The solubility in water is about 10 times that of cisplatin, and it changes the distribution of the drug in the kidneys.
Its nephrotoxicity and gastrointestinal side effects are relatively high.
Cisplatin has been reduced.
Its dose-limiting toxicity is thrombocytopenia caused by bone marrow suppression, and nedaplatin is still effective in patients who are resistant to cisplatin.
Figure 3 The chemical structure of Nidaplatin ■ The third-generation platinum oxaliplatin was approved by the US FDA in 2002.
Oxaliplatin maintains the cis-structure of cisplatin and introduces a hydrophobic diaminocyclohexane ligand to prevent the binding of repair proteins to DNA.
Therefore, oxaliplatin becomes the first platinum resistant to drug resistance in tumor cells.
Class of drugs.
Oxaliplatin is more toxic to the gastrointestinal tract, liver, kidney and bone marrow than cisplatin and carboplatin, and it is well tolerated.
Oxaliplatin is the first platinum drug with a significant effect on colon cancer.
It is often used clinically in combination with 5-fluorouracil or capecitabine and calcium leucovorin.
In addition, oxaliplatin also has a good effect on non-small cell lung cancer, gastric cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, malignant lymphoma, esophageal cancer, liver cancer and head and neck tumors.
Figure 4 The chemical structure of oxaliplatin Table 1 How are platinum drugs compared to platinum drugs to fight cancer? Platinum anticancer drugs are cell cycle non-specific drugs.
In the early studies of platinum drugs, DNA was determined to be the main one Cell target.
The three platinum drugs that are currently popular in cancer treatment-cisplatin, carboplatin and oxaliplatin, all impair normal DNA function by producing monoadducts and DNA crosslinks.
They are generally considered to be close to alkylating agents.
Its electrophilicity leads to reaction with nucleophilic residues of DNA molecules, thereby mediating tumor cell necrosis or apoptosis.
Many cancers have defective DNA repair, a feature that also leads to secondary drug resistance.
Resistance mechanism is one of the main research areas of platinum compounds.
Drug accumulation, drug efflux, factors that prevent the drug from interacting with its target, ways to eliminate target damage, and factors and pathways involved in cell response to injury have been widely discussed in preclinical models.
In addition, the genome-wide functional screening method has revealed new discoveries in the absorption of platinum-based drugs.
About half of cisplatin and carboplatin can enter cells through the widely expressed volume-regulated negative ion channel (VRAC).
Therefore, this heterogeneous channel may be a useful biomarker.
In addition, platinum-based treatments may be improved in the future by optimizing the combination of immunotherapy, side effects management, and the use of nano-delivery devices.
In the next few years, platinum drugs may remain the cornerstone of cancer treatment standards.
Figure 5 The mechanism of action of platinum-based drugs The differences in the DNA damage response (DDR) of the newly developed multiple platinum-based preparations provide a useful explanation for drug sensitivity.
Most cancers have lost a key DDR pathway during evolution.
Therefore, tumor cells that lack proper DNA repair will die.
The normal cells of the body can still cope with this damage.
For example: DNA cross-linking caused by platinum drugs.
Among the different DDR mechanisms, the homologous recombination (HR) pathway is of particular interest because it mediates the error-free repair of cytotoxic double-strand breaks.
Because HR-deficient tumors are highly sensitive to DNA cross-linking agents, high-dose carboplatin-based chemotherapy can cure BRCA1 or BRCA2-related metastatic breast cancer.
Such an intensive treatment plan is suitable for young people and people with strong physique, but it is also controversial.
The new generation of platinum compounds may have fewer side effects and have sufficient DNA cross-linking activity to kill HR-deficient tumors.
Figure 6 Platinum compounds and their preparations.
Platinum drugs developed based on the mechanism of action are different from existing clinical drugs: including multinuclear platinum agents, monofunctional derivative preparations and platinum (IV) prodrugs.
There are many differences between these platinum preparations and traditional platinum preparations.
Multinuclear platinum agents, such as triplatin, have a unique long-acting mechanism of coordination and electrostatic interaction with molecules to generate phosphate clamps, a ring structure.
Another way to further optimize is to improve drug delivery.
Use nano delivery particles and nano formulations or tumor targeting polymers.
Liposomal cisplatin formulations, such as lipoplatin: Encapsulation of platinum-based agents into liposomes can increase bioavailability and reduce toxicity.
Other preclinical research methods aim to improve the release efficiency, release profile and storage stability of tumor tissue-targeted liposome capsules.
For example, in rats with bladder cancer, the structure of polyethylene glycol liposomes increases the exposure time of the tumor to the drug and reduces the toxicity.
Where does the platinum family go in the future? The discovery of new mechanisms of sensitivity or resistance to platinum compounds provides valuable information for drug development and can be further applied to the clinic.
Platinum compounds are quite ancient drugs, and it is unreasonable to conclude prematurely.
However, new preclinical and clinical observations, especially with regard to potential therapeutic effects and clinically relevant mechanisms of drug resistance, protection of side effects and immunomodulatory effects are ongoing.
Further studies on the interaction of platinum drugs with biomolecules other than DNA may reveal new mechanisms.
A new preclinical model has been established, which can be used to protect patients from the side effects caused by cisplatin.
Research linking the efficacy of chemotherapy (including platinum-based therapies) to microbes provides a new window for future development.
Evidence shows that bacteria control the response to treatment by regulating the microenvironment.
The definition of the active molecular characteristics of platinum compounds and the characteristics of patients with expected benefits, including understanding of concomitant treatments (antibiotics and effects on the microbiota, glucocorticoids, etc.
) will help optimize platinum-based anti-tumor treatments.
References: [1]Rottenberg Sven, Disler Carmen, Perego Paola.
The rediscovery of platinum-based cancer therapy.
[J].
Nature reviews.
Cancer,2021,21(1).
[2]Kelland, L.
The resurgence of platinum-based cancer chemotherapy.
Nat.
Rev.
Cancer 7, 573–584 (2007).
[3]Lippard, SJ New chemistry of an old molecule: cis-[Pt(NH3)2Cl2.
Science 218, 1075–1082 (1982 )[4]Wang Yujing,Xiong Huijuan,Wu Shasha,Zhou Xuewen,Wang Xiaobo.
The research status and progress of platinum anticancer drugs[J].
Journal of Hubei University of Science and Technology (Medical Edition),2020,34(03):270-273.
[5]Sun Piao, Ding Yang, Zhou Jianping.
Research progress of platinum anti-tumor drug nano-delivery system[J].
Chinese Journal of Pharmaceutical Industry, 2019, 50(12): 1383-1392.
Expert profile Liu Jinglin, Tianjin Medical University Tumor Introduction to the Department of Pharmacists in the Department of Pharmacy of the Hospital There are 82 people in the Department of Pharmacy of Tianjin Cancer Hospital, who are responsible for the supply and adjustment of clinical and scientific research drugs, as well as clinical pharmacy services and pharmacy management. Under the Department of Pharmacy, there are Chinese and Western pharmacies, inpatient pharmacies, intravenous fluid distribution centers, daytime dispensing, clinical pharmacy and other departments, equipped with outpatient automatic medicine dispensers, granule automatic dispensing machines, inpatient automatic oral medicine dispensers, and intravenous liquid dispensing Automatic equipment such as automatic sorter has a complete and scientific hardware management system.
We pass pre-prescription review; prescription and doctor's advice review work; through clinical pharmacists participating in the management of drug treatment in clinical departments to ensure the safe and reasonable medication.
In addition, the pharmacy research work should be carried out in accordance with the actual needs of clinical practice, and gradually form the characteristics of hospital pharmacy that combines clinical and scientific research.
Through the continuous improvement of the hardware and software system, pharmacy as a discipline is gradually developing towards precision and refinement.
Hospital pharmacy provides patients with all-round, full-chain pharmacy services, and escorts the realization of reasonable, safe and effective medication.
Wonderful review of past issues ☑ Do you know that these medicines cannot be used together? ☑ What should I pay attention to when treating NSCLC with ALK-TKI? One article to understand! ☑ Wonderful! If Cao Cao had a brain tumor with unbearable pain, what would Hua Tuo do? ☑ How to arrange diet and daily life for targeted and immunotherapy patients? Super full guide is here
