Topotecan, sold under the brand name Hycamtin among others, is a
chemotherapeutic agent medication that is a
topoisomerase inhibitor. It is a synthetic, water-soluble
analog of the natural chemical compound
camptothecin. It is used in the form of its
hydrochloride salt
In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...
to treat
ovarian cancer,
lung cancer
Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...
and other cancer types.
After
GlaxoSmithKline
GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...
received final
FDA approval for topotecan on 15 October 2007, it became the first topoisomerase I inhibitor for oral use.
Uses
*
Ovarian cancer (FDA May 1996).
*
Cervical cancer (FDA June 2006).
*
Small cell lung carcinoma (SCLC) (FDA Oct 2007).
Experimental uses
As of 2016, experiments were under way for
neuroblastoma,
brainstem glioma,
Ewing's sarcoma and
Angelman's syndrome. In addition, topotecan is experimentally treating
non-small cell lung cancer,
colorectal cancer-,
breast cancer
Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
,
non-Hodgkin lymphoma,
endometrial cancer
Endometrial cancer is a cancer that arises from the endometrium (the epithelium, lining of the uterus or womb). It is the result of the abnormal growth of cells (biology), cells that can invade or spread to other parts of the body. The first s ...
, and
oligodendroglioma
Oligodendrogliomas are a type of glioma that are believed to originate from the oligodendrocytes of the brain or from a oligodendrocyte progenitor cell, glial precursor cell. They occur primarily in adults (9.4% of all primary brain and central ne ...
.
Angelman's syndrome
Angelman's syndrome is a neuro-genetic disorder characterized by severe developmental delays, seizures, speech impairments and physical impairments. It is an epigenetic disease and other treatments focus on symptoms. It is caused by a deletion or mutation of the maternal allele for the
ubiquitin protein ligase E3A (UBE3A).
UBE3A is expressed in most body tissues. However, in neurons only the maternal copy of the gene is expressed. UBE3A is located on
chromosome 15 and the paternal copy for the gene is genetically imprinted and is silenced by an
antisense RNA
Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and ...
transcript. The maternal copy control center of the gene is methylated, suppressing transcription in the antisense direction while the paternal copy control center is unmethylated.
Treatment involves unsilencing the paternal allele allowing the normal paternal UBE3A allele to be transcribed. UBE3A, in normal function, adds ubiquitin chains to proteins to target unnecessary or damaged proteins for degradation by the
proteasome.
16 topoisomerase inhibitors unsilence paternal UBE3A. Topoisomerases are enzymes that regulate the unwinding of DNA. Of these 16 inhibitors, topotecan was found to induce the strongest upregulation of UBE3A.
The enzymes bind to the DNA and cut the phosphate backbone, allowing the DNA to be unwound. Topotecan unsilences the paternal UBE2A allele by reducing the transcription of an antisense transcript. Topotecan inhibits topoisomerase I restoring UBE3A levels to wild-type range in cultured mince neurons.
Transgenic mice with a fluorescently tagged UBE3A were used to test the effectiveness of unsilencing the paternal copy.
When tested on mice ''in vivo'', topotecan affected the
hippocampus
The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
,
striatum
The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...
and
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
but not the
cerebellum
The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...
unless a higher dose was administered (21.6 micrograms/hour for five days). The study suggested that the topoisomerase inhibitors have the potential to produce a normally functioning UBE3A protein. Most symptoms due to Angelman's syndrome are traditionally treated by
speech therapy
Speech is the use of the human voice as a medium for language. Spoken language combines vowel and consonant sounds to form units of meaning like words, which belong to a language's lexicon. There are many different intentional speech acts, suc ...
,
physical therapy
Physical therapy (PT), also known as physiotherapy, is a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease preventio ...
and
occupational therapy
Occupational therapy (OT), also known as ergotherapy, is a healthcare profession. Ergotherapy is derived from the Greek wiktionary:ergon, ergon which is allied to work, to act and to be active. Occupational therapy is based on the assumption t ...
.
Anti-seizure medication is often prescribed as seizures are a common symptom of Angelman's syndrome. These treatments target only symptoms.
This drug has been administered to cancer patients. It was well tolerated when administered to pediatric and adult patients.
Mechanism of action
Topotecan is a semi-synthetic derivative of
camptothecin. Camptothecin is a natural product extracted from the bark of the tree
''Camptotheca acuminata''. Topoisomerase-I is a nuclear enzyme that relieves torsional strain in
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
by opening single strand breaks. Once topoisomerase-I creates a single strand break, the DNA can rotate in front of the advancing replication fork. In physiological environments, topotecan is in equilibrium with its inactive carboxylate form.
Topotecan's active lactone form
intercalates between DNA bases in the topoisomerase-I cleavage complex.
The binding of topotecan in the cleavage complex prevents topoisomerase-I from religating the nicked DNA strand after relieving the strain.
This intercalation therefore traps the topoisomerase-I in the cleavage complex bound to the DNA.
When the replication-fork collides with the trapped topoisomerase-I, DNA damage occurs.
The unbroken DNA strand breaks and mammalian cells cannot efficiently repair these double strand breaks. The accumulation of trapped topoisomerase-I complexes is a known response to apoptotic stimuli. This disruption prevents DNA replication and ultimately leads to cell death. This process leads to breaks in the DNA strand resulting in
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
. Administration of topotecan down-regulates its target, topoisomerase-I; therefore, it is dosed to maximize efficacy and minimize related toxicity.
Topotecan is often given in combination with
paclitaxel as first line treatment for extensive-stage
small-cell lung cancer.
Side effects
* Myelosuppression, specifically neutropenia, leukopenia, anemia, and thrombocytopenia
* Diarrhea, nausea, vomiting, stomatitis, and constipation
* Increased susceptibility to infections
* Asthenia
Generic versions
Two generic versions have been approved in the European Union. In Nov 2010 the US FDA approved a generic version.
References
Sources
*
External links
NCI Drug Dictionary Definition of TopotecanTopotecan Hydrochloride
{{Authority control
Lactams
Delta-lactones
Pyranoindolizinoquinolines
Topoisomerase inhibitors
Drugs developed by GSK plc
Drugs developed by Novartis
Dimethylamino compounds