Cancer curative agents Flashcards
…………is a quinoline alkaloid from a Chinese tree Camptotheca acuminate?
Camptothecin
Structure of Camptothecin
It has a pentacyclic structure and is a somewhat planar structure with a lactone ring that is important for the biological antitumour activity
Camptothecin is________ and __________ which has restricted its use until recently. True/false
Camptothecin is toxic and has poor aqueous solubility which has restricted its use until recently. True/false
Camptothecin conjugated with _______ as ____________ is now being used for various types of cancers.
True/False
Camptothecin conjugated with cyclodextrin as nanoparticles is now being used for various types of cancers.
MOA of Camptothecin
It has been found to display broad-spectrum antitumour activity on ______, ____, ______-, and _____cancers. It kills cells in the ______. It inhibits the enzyme ___________, which is involved with DNA replication.
It __________ the complex between DNA and the enzyme, prevents ____________ and ____________. In vitro testing showed excellent activity against _______, but in vivo was disappointing and there were number of side-effects _______.
It has been found to display broad-spectrum antitumour activity on gastric, rectal, colon, and bladder cancers. It kills cells in the ‘S’ phase. It inhibits the enzyme topoisomerase I, which is involved with DNA replication.
It stabilizes the complex between DNA and the enzyme, prevents replication resulting in DNA cleavage and cell death. In vitro testing showed excellent activity against leukaemia cells, but in vivo was disappointing and there were number of side-effects (long half-life).
List two water-soluble semi-synthetic derivatives of Camptothecin
(Hycamtin®)
(Camptosar®)
topotecan (Hycamtin®) and irinotecan (Camptosar®).
What is the therapeutic use of Topotecan?
following unsuccessful treatment with either _______ or ______compounds. Is given with ________ for cancer of the cervix. It has a __________
is used for relapsed small-cell lung cancer (IV or oral) and in advanced ovarian cancer (injection) following unsuccessful treatment with either paclitaxel or platinum-based compounds. Is given with cisplatin for cancer of the cervix. It has a shorter half-life.
What is the use of Irinotecan?
Irinotecan is a prodrug. Hydrolysis occurs as indicated and the resulting compound is ______ more potent. It is given by ________. It is used with and without ___________ for advanced __________. It can cause diarrhoea. Combination of treatment with other _____________
Irinotecan is a prodrug. Hydrolysis occurs as indicated and the resulting compound is 1000 times more potent. It is given by intravenous infusion. It is used with and without 5-fluorouracil for advanced colorectal cancer. It can cause diarrhoea. Combination of treatment with other anti-cancer agents
Facts about the use of Euphorbia peplus in Austrialia
6
Euphorbia peplus which grows wild in England has traditionally been used in Australia for a number of conditions which include asthma and catarrh, as a laxative, and topical treatment for warts, corns, and skin cancers.
Facts about in vitro studies of E. peplus extract
Initial in vitro studies of E. peplus extract against a number of _____________ showed an interesting effect of ________ poly-dendritic type cells changed to bipolar ones, suggesting that it was specific of compounds in the plant. Further work on mice with topical tumours demonstrated therapeutic potential. Many of the tumours after treatment with E. peplus extract started to show ________ and ______ within 24 h which _________- within 48 hours, followed by formation of a scab and healing. Clinical studies with non-melanoma skin cancer patients gave very good success rates of cure. Extensive investigation ensued to isolate and demonstration that the active compound is a ___________ composed of ingenol and angelic acid named_______________.
Initial in vitro studies of E. peplus extract against a number of tumour cell lines showed an interesting effect of melanoma poly-dendritic type cells changed to bipolar ones, suggesting that it was specific of compounds in the plant. Further work on mice with topical tumours demonstrated therapeutic potential. Many of the tumours after treatment with E. peplus extract started to show erythema and bruising within 24 h which then turned black within 48 hours, followed by formation of a scab and healing. Clinical studies with non-melanoma skin cancer patients gave very good success rates of cure. Extensive investigation ensued to isolate and demonstration that the active compound is a diterpene ester composed of ingenol and angelic acid named ingenol mebutate.
What compound has been formulated as a gel and is being marketed as Picato® for the treatment of actinic keratosis, a UV-induced skin cancer which has potential to become invasive?
Ingenol mebutate compound
Ingenol mebutate is currently isolated from the plant. True/false?
True
synthetic/semisynthetic methods to produce Ingenol mebutate have been explored and one that commences from………….
the monoterpene (+)-3-carene (obtained from turpentine)
Facts about Podophyllum resin
obtained from _________. is a source of _________. The Indian species contains relatively more ________ and podophyllotoxin.
Podophyllotoxin was first isolated in 1880 and the structure identified in 1951. It has a _________. It acts as in a similar way to ___________ and interferes with the spindle formation and hence is________ that are dividing.
obtained from Podophyllum spp. is a source of podophyllotoxin. The Indian species contains relatively more resin and podophyllotoxin.
Podophyllotoxin was first isolated in 1880 and the structure identified in 1951. It has a flat ring structure. It acts as in a similar way to colchicine and interferes with the spindle formation and hence is toxic to cells that are dividing.
Podophyllotoxin displays anti-cancer activity but it also produces many side effects. True or False?
True
How molecules which are still potent but with less side effects are obtained
,structure-activity studies of numerous analogues was undertaken to find molecules which are still potent but with less side effects. Systematic changes within each of the rings have involved e.g. derivatives with changes to rings A and B did not show any activity, whilst an attachment of sugar type molecules to ring C gave relatively more potent compounds (two compounds [etoposide and teniposide] with these features are being used clinically), and the trans fusion of ring D to ring C was found be essential for activity (under basic conditions the cis form is formed and this product is not active).
A phosphate ester of etoposide (_______), administered____, is ______. and is a pro-drug converted to _______.
A phosphate ester of etoposide (etopophos), administered IV, is water sol. and is a pro-drug converted to etoposide.
Etoposide and etopophos are both ………
Glycosides
Etoposide is active against what type of illness?
REMEMBER THE HSL
Etoposide is active against testicular cancer, Hodgkin’s disease, small-cell lung cancer, types of leukemia, and other cancers. It is combined with other agents.
Mechanism of Action of Etoposide
Etoposide inhibits DNA topoisomerase II
Mechanism of action of Podophyllotoxin
podophyllotoxin binds to tubulin and inhibits microtubule formation.
Facts about Teniposide
Teniposide is equally potent and particularly useful against lymphoblastic leukaemia in both adults and children, but is less widely used
A diterpene isolated from T. brevifolia as part of the NCI project that has made a great impact in the treatment of breast and ovarian cancers is known as ?
Taxol® (paclitaxel)
Reasons why Paclitaxel nearly did not get developed into a useful drug
Paclitaxel is produced in very low amounts in T. brevifolia and the tree takes many years to mature – there would never be enough to satisfy world demand.
Paclitaxel has a very complicated structure and hence is not easily synthesized.
Formulations were difficult due to lack of water solubility.
Large scale production of Paclitaxel
A semi-synthetic process was initially used where ___________(which acted as an intermediate) from _________was converted to paclitaxel.
The species T. brevifolia could not be relied upon. A semi-synthetic process was initially used where 10-deacetylbaccatin III (which acted as an intermediate) from Taxus baccata was converted to paclitaxel.
Presently, plant tissue culture method is used for large-scale production
Indication of Paclitaxel
________(nanoparticle albumin-bound) is being used for advanced __________and as monotherapy for _______ cancer. Being bound to _______ reduces hypersensitivity reactions to paclitaxel.
Paclitaxel is available for infusion and indicated for a number of types of cancers including breast and ovarian cancers and in combination with other drugs.
Nab-paclitaxel (nanoparticle albumin-bound) is being used for advanced pancreatic cancer and as monotherapy for metastatic breast cancer. Being bound to albumin reduces hypersensitivity reactions to paclitaxel.
Therapeutic use of Docetaxel (Taxotere®)
Docetaxel (Taxotere®) is another compound that is being used clinically for advanced breast cancer and non-small cell lung cancer. Docetaxel has greater affinity for _____ than paclitaxel and hence is more _____, and also induces ________ and inhibits __________ in cancer cells. It is being formulated as a ______ preparation for treating solid tumours.
Docetaxel (Taxotere®) is another compound that is being used clinically for advanced breast cancer and non-small cell lung cancer. Docetaxel has greater affinity for microtubules than paclitaxel and hence is more potent, and also induces apoptosis and inhibits angiogenesis in cancer cells. It is being formulated as a micelle preparation for treating solid tumours.
What drug is indicated for metastatic prostate cancer?
____ is being used for metastatic prostate cancer. It stimulates formation of ________ structures and also then inhibits its ______, thus stopping _______.
Cabazitaxel is being used for metastatic prostate cancer. It stimulates formation of microtubule structures and also then inhibits its deconstruction, thus stopping cell division.
Facts about Catharanthus roseus
Catharanthus roseus, commonly called the _________ was recognised for its anti-cancer properties in the 1950’s. The active compounds, _________, and _________ were isolated in 1961 and the clinical trials followed thereafter
Catharanthus roseus, commonly called the Madagascar perwinkle was recognised for its anti-cancer properties in the 1950’s. The active compounds, vincristine, and vinblastine were isolated in 1961 and the clinical trials followed thereafter
Facts about vincristine and vinblastine
Both vincristine and vinblastine are indole alkaloids and have a complex, dimeric structure. The structural difference between the two is very small. Vinblastine has a __________ while vincristine has a _________. These are small differences but have a significant effect on the anti-cancer properties and the toxicity displayed by the two compounds.
Both vincristine and vinblastine are indole alkaloids and have a complex, dimeric structure. The structural difference between the two is very small. Vinblastine has a N-methyl group while vincristine has a N-formyl group. These are small differences but have a significant effect on the anti-cancer properties and the toxicity displayed by the two compounds.
MOA of both Vincristine and Vinblastine
The mode of action of both compounds is by inhibiting the formation of microtubule from tubulin and thus preventing cell division. The actual binding site is not known but is known to be different from the one that colchicine and taxoids bind to.
Uses of Vincristine
COMPARISM WITH VINBLASTIN
AFFINITY
USES OF VINBLASTIN?
Vincristine is used for acute lymphoblastic leukaemias in children, lymphomas, small cell lung cancer, cervical and breast cancers. It has better anti-cancer activity than vinblastine but it is also more neurotoxic due to its affinity for axon microtubules. Vinblastine is used with other anti-cancer agents to treat bladder and breast cancers, and as well Hodgkin’s disease.
_______________ is one such compound that has been approved for treatment of non-small cell lung cancer and advanced breast cancer.
Vinorelbine (Navelbine®) is one such compound that has been approved for treatment of non-small cell lung cancer and advanced breast cancer.
Other modifications to the structure have made possible ________, which is being used clinically for acute leukaemia, lymphomas and breast and lung cancers.
vindesine (Eldesine®)
State the amount of alkaloid content in the C. roseus
The amount of alkaloid content in the C. roseus is very small (vincristine: 0.0003%; vinblastine: 0.01% dry weight).
The plant is cultivated but this is still not enough commercially to satisfy demand, especially since vincristine is in more demand than vinblastine. The latter is chemically converted to vincristine by oxidation of the N-methyl group.
Facts about Cephalostatins
Cephalostatins, from a marine worm, are alkaloids and a group of compounds that have been investigated for their anticancer potential. Of these, cephalostatin 1 has been reported to have potent in vitro cancer cell growth inhibitor properties for several types of cancers. It triggers apoptosis by a unique mechanism involving mitochondria. Further work is ongoing.
Examples of some of the well-known compounds from plants that display anti-cancer properties.
mistletoe (Viscum album) produces proteins that interact with ribosomes deactivating them and thus displaying anticancer activity.
