Carboplatin
Encyclopedia
Carboplatin, or cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II) (trade names Paraplatin and Paraplatin-AQ) is a chemotherapy
drug
used against some forms of cancer
(mainly ovarian carcinoma, lung, head and neck cancers). It was introduced in the late 1980s and has since gained popularity in clinical treatment due to its vastly reduced side-effects compared to its parent compound cisplatin
. Cisplatin and carboplatin, as well as oxaliplatin
, interact with DNA
, akin to the mechanism of alkylating agents
.
gained Food and Drug Administration
(FDA) approval for carboplatin, under the brand name Paraplatin, in March 1989. Starting in October 2004, generic versions of the drug became available.
ligand
, which are the leaving groups in cisplatin. It exhibits lower reactivity and slower DNA binding kinetics, although it forms the same reaction products in vitro at equivalent doses with cisplatin. Unlike cisplatin, carboplatin may be susceptible to alternative mechanisms. Some results show that cisplatin and carboplatin cause different morphological changes in MCF-7 cell lines while exerting their cytotoxic behaviour. The diminished reactivity limits protein-carboplatin complexes, which are excreted. The lower excretion rate of carboplatin means that more is retained in the body, and hence its effects are longer lasting (a retention half-life of 30 hours for carboplatin, compared to 1.5-3.6 hours in the case of cisplatin).
of carboplatin with DNA:
The former is more accepted owing to the similarity of the leaving groups with its predecessor cisplatin, while the latter hypothesis envisages a biological activation mechanism to release the active Pt2+ species.
effects. Nausea
and vomiting
are less severe and more easily controlled.
The main drawback of carboplatin is its myelosuppressive effect. This causes the blood
cell
and platelet
output of bone marrow in the body to decrease quite dramatically, sometimes as low as 10% of its usual production levels. The nadir of this myelosuppression usually occurs 21–28 days after the first treatment, after which the blood cell and platelet levels in the blood begin to stabilize, often coming close to its pre-carboplatin levels. This decrease in white blood cell
s (neutropenia
) can cause complications, and is sometimes treated with drugs like filgrastim
. The most notable complication of neutropenia is increased probability of infection by opportunistic organisms, which necessitates readmission to hospital and treatment with antibiotic
s.
Carboplatin is less potent than cisplatin; depending on the strain of cancer, carboplatin may only be 1/8 to 1/45 as effective. The clinical standard of dosage of carboplatin is usually a 4:1 ratio compared to cisplatin; that is, for a dose that usually requires a particular dose of cisplatin, four times more carboplatin is needed to achieve the same effectiveness. The stable property of carboplatin is a mixed blessing: once uptake of the drug occurs, its retention half-life is considerably longer than cisplatin, but it is also this inertness that causes carboplatin to go right through the human body, and up to 90% of the carboplatin given can be recovered in urine.
The effectiveness of carboplatin can be increased by first incubating carboplatin in a sodium chloride
(NaCl) solution. After 24 hours, an analysis is performed on the solution by separating the compounds by thin-layer chromatography
(TLC). The TLC isolates cisplatin, carboplatin, and several platinum by-products in the solution. Numerous trials have shown a trend that the survival rate of E. coli dropped dramatically as the molarity of the NaCl incubating solution increased. The treated E. coli also showed decreased amounts of alkaline phosphatase, a protein indicator of cellular size. This suggests that as this incubated carboplatin solution is administered to cells, they began to shrink and eventually die; apparently by the same mechanism that cisplatin works.
. GemCarbo chemotherapy is usually conducted as a day patient treatment, involving a blood test the day before. The drugs are administered by infusion. The GemCarbo regimen is given as a 21-day cycle. On the first day of treatment the patient is given both the gemcitabine and carboplatin. On the same day of the following week (day eight) there is a drip of gemcitabine only. There then follows a rest period of two weeks which completes one cycle of chemotherapy. The next cycle of treatment is given after a rest period, ends three weeks after the first injection. Usually 4–6 cycles of treatment are given over a period of 3–4 months to complete a full course of treatment. This treatment may prevent the further spread of the cancer or in some cases may reduce the size of the tumor
between 20%-80%, depending upon the individual.
Carboplatin has also been used to treat testicular cancer patients with stage 1 seminoma. Recent research indicates that this treatment is more effective and has fewer side effects than adjuvant radiotherapy. It is as effective as radiotherapy at preventing development of seminoma in the remaining testicle.
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
used against some forms of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
(mainly ovarian carcinoma, lung, head and neck cancers). It was introduced in the late 1980s and has since gained popularity in clinical treatment due to its vastly reduced side-effects compared to its parent compound cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
. Cisplatin and carboplatin, as well as oxaliplatin
Oxaliplatin
Oxaliplatin is a coordination complex that is used in cancer chemotherapy. These platinum-based drugs are usually classified as alkylating agents, although they are not actually alkylating groups ....
, interact with DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, akin to the mechanism of alkylating agents
Alkylating antineoplastic agent
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....
.
History
Carboplatin was discovered and developed at the Institute of Cancer Research in London. Bristol-Myers SquibbBristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...
gained Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approval for carboplatin, under the brand name Paraplatin, in March 1989. Starting in October 2004, generic versions of the drug became available.
Chemistry
In terms of its structure, carboplatin differs from cisplatin in that it has a bidentate dicarboxylate (CBDCA) ligand in place of the two chlorideChloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
, which are the leaving groups in cisplatin. It exhibits lower reactivity and slower DNA binding kinetics, although it forms the same reaction products in vitro at equivalent doses with cisplatin. Unlike cisplatin, carboplatin may be susceptible to alternative mechanisms. Some results show that cisplatin and carboplatin cause different morphological changes in MCF-7 cell lines while exerting their cytotoxic behaviour. The diminished reactivity limits protein-carboplatin complexes, which are excreted. The lower excretion rate of carboplatin means that more is retained in the body, and hence its effects are longer lasting (a retention half-life of 30 hours for carboplatin, compared to 1.5-3.6 hours in the case of cisplatin).
Mode of action
Two theories exist to explain the molecular mechanism of actionMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
of carboplatin with DNA:
- Aquation, or the like-cisplatin hypothesis.
- ActivationActivationActivation in chemical sciences generally refers to the process whereby something is prepared or excited for a subsequent reaction.- Chemistry :...
, or the unlike-cisplatin hypothesis.
The former is more accepted owing to the similarity of the leaving groups with its predecessor cisplatin, while the latter hypothesis envisages a biological activation mechanism to release the active Pt2+ species.
Side-effects
Relative to cisplatin, the greatest benefit of carboplatin is its reduced side effects, particularly the elimination of nephrotoxicNephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
effects. Nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
are less severe and more easily controlled.
The main drawback of carboplatin is its myelosuppressive effect. This causes the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
and platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
output of bone marrow in the body to decrease quite dramatically, sometimes as low as 10% of its usual production levels. The nadir of this myelosuppression usually occurs 21–28 days after the first treatment, after which the blood cell and platelet levels in the blood begin to stabilize, often coming close to its pre-carboplatin levels. This decrease in white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s (neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
) can cause complications, and is sometimes treated with drugs like filgrastim
Filgrastim
Filgrastim is a granulocyte colony-stimulating factor analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. ...
. The most notable complication of neutropenia is increased probability of infection by opportunistic organisms, which necessitates readmission to hospital and treatment with antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s.
Carboplatin is less potent than cisplatin; depending on the strain of cancer, carboplatin may only be 1/8 to 1/45 as effective. The clinical standard of dosage of carboplatin is usually a 4:1 ratio compared to cisplatin; that is, for a dose that usually requires a particular dose of cisplatin, four times more carboplatin is needed to achieve the same effectiveness. The stable property of carboplatin is a mixed blessing: once uptake of the drug occurs, its retention half-life is considerably longer than cisplatin, but it is also this inertness that causes carboplatin to go right through the human body, and up to 90% of the carboplatin given can be recovered in urine.
The effectiveness of carboplatin can be increased by first incubating carboplatin in a sodium chloride
Sodium chloride
Sodium chloride, also known as salt, common salt, table salt or halite, is an inorganic compound with the formula NaCl. Sodium chloride is the salt most responsible for the salinity of the ocean and of the extracellular fluid of many multicellular organisms...
(NaCl) solution. After 24 hours, an analysis is performed on the solution by separating the compounds by thin-layer chromatography
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....
(TLC). The TLC isolates cisplatin, carboplatin, and several platinum by-products in the solution. Numerous trials have shown a trend that the survival rate of E. coli dropped dramatically as the molarity of the NaCl incubating solution increased. The treated E. coli also showed decreased amounts of alkaline phosphatase, a protein indicator of cellular size. This suggests that as this incubated carboplatin solution is administered to cells, they began to shrink and eventually die; apparently by the same mechanism that cisplatin works.
GemCarbo chemotherapy for lung cancer
GemCarbo chemotherapy (consisting of gemcitabine, also known as Gemzar, and carboplatin) is used to treat several different types of cancer, but is most commonly used to treat lung cancerLung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
. GemCarbo chemotherapy is usually conducted as a day patient treatment, involving a blood test the day before. The drugs are administered by infusion. The GemCarbo regimen is given as a 21-day cycle. On the first day of treatment the patient is given both the gemcitabine and carboplatin. On the same day of the following week (day eight) there is a drip of gemcitabine only. There then follows a rest period of two weeks which completes one cycle of chemotherapy. The next cycle of treatment is given after a rest period, ends three weeks after the first injection. Usually 4–6 cycles of treatment are given over a period of 3–4 months to complete a full course of treatment. This treatment may prevent the further spread of the cancer or in some cases may reduce the size of the tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
between 20%-80%, depending upon the individual.
Current events
A recent study in mutant mice suggests that in the subset of women with breast cancer due to BRCA1 and BRCA2 genes (these cause a variety of familial breast cancer) carboplatin may be as much as 20 times more effective than the usual breast cancer treatments. However, similar data in humans has not yet been shown.Carboplatin has also been used to treat testicular cancer patients with stage 1 seminoma. Recent research indicates that this treatment is more effective and has fewer side effects than adjuvant radiotherapy. It is as effective as radiotherapy at preventing development of seminoma in the remaining testicle.