Cancer curative agents

Question 1

…………is a quinoline alkaloid from a Chinese tree Camptotheca acuminate?

Answer 1

Camptothecin

Question 2

Structure of Camptothecin

Answer 2

It has a pentacyclic structure and is a somewhat planar structure with a lactone ring that is important for the biological antitumour activity

Question 3

Camptothecin is________ and __________ which has restricted its use until recently. True/false

Answer 3

Camptothecin is toxic and has poor aqueous solubility which has restricted its use until recently. True/false

Question 4

Camptothecin conjugated with _______ as ____________ is now being used for various types of cancers.

True/False

Answer 4

Camptothecin conjugated with cyclodextrin as nanoparticles is now being used for various types of cancers.

Question 5

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 _______.

Answer 5

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).

Question 6

List two water-soluble semi-synthetic derivatives of Camptothecin

(Hycamtin®)

(Camptosar®)

Answer 6

topotecan (Hycamtin®) and irinotecan (Camptosar®).

Question 7

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 __________

Answer 7

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.

Question 8

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 _____________

Answer 8

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

Question 9

Facts about the use of Euphorbia peplus in Austrialia

6

Answer 9

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.

Question 10

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_______________.

Answer 10

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.

Question 11

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?

Answer 11

Ingenol mebutate compound

Question 12

Ingenol mebutate is currently isolated from the plant. True/false?

Answer 12

True

Question 13

synthetic/semisynthetic methods to produce Ingenol mebutate have been explored and one that commences from………….

Answer 13

the monoterpene (+)-3-carene (obtained from turpentine)

Question 14

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.

Answer 14

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.

Question 15

Podophyllotoxin displays anti-cancer activity but it also produces many side effects. True or False?

Answer 15

True

Question 16

How molecules which are still potent but with less side effects are obtained

Answer 16

,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).

Question 17

A phosphate ester of etoposide (_______), administered____, is ______. and is a pro-drug converted to _______.

Answer 17

A phosphate ester of etoposide (etopophos), administered IV, is water sol. and is a pro-drug converted to etoposide.

Question 18

Etoposide and etopophos are both ………

Answer 18

Glycosides

Question 19

Etoposide is active against what type of illness?

REMEMBER THE HSL

Answer 19

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.

Question 20

Mechanism of Action of Etoposide

Answer 20

Etoposide inhibits DNA topoisomerase II

Question 21

Mechanism of action of Podophyllotoxin

Answer 21

podophyllotoxin binds to tubulin and inhibits microtubule formation.

Question 22

Facts about Teniposide

Answer 22

Teniposide is equally potent and particularly useful against lymphoblastic leukaemia in both adults and children, but is less widely used

Question 23

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 ?

Answer 23

Taxol® (paclitaxel)

Question 24

Reasons why Paclitaxel nearly did not get developed into a useful drug

Answer 24

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.

Question 25

Large scale production of Paclitaxel

A semi-synthetic process was initially used where ___________(which acted as an intermediate) from _________was converted to paclitaxel.

Answer 25

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

Question 26

Indication of Paclitaxel

________(nanoparticle albumin-bound) is being used for advanced __________and as monotherapy for _______ cancer. Being bound to _______ reduces hypersensitivity reactions to paclitaxel.

Answer 26

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.

Question 27

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.

Answer 27

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.

Question 28

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 _______.

Answer 28

Cabazitaxel is being used for metastatic prostate cancer. It stimulates formation of microtubule structures and also then inhibits its deconstruction, thus stopping cell division.

Question 29

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

Answer 29

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

Question 30

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.

Answer 30

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.

Question 31

MOA of both Vincristine and Vinblastine

Answer 31

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.

Question 32

Uses of Vincristine

COMPARISM WITH VINBLASTIN

AFFINITY

USES OF VINBLASTIN?

Answer 32

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.

Question 33

_______________ is one such compound that has been approved for treatment of non-small cell lung cancer and advanced breast cancer.

Answer 33

Vinorelbine (Navelbine®) is one such compound that has been approved for treatment of non-small cell lung cancer and advanced breast cancer.

Question 34

Other modifications to the structure have made possible ________, which is being used clinically for acute leukaemia, lymphomas and breast and lung cancers.

Answer 34

vindesine (Eldesine®)

Question 35

State the amount of alkaloid content in the C. roseus

Answer 35

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.

Question 36

Facts about Cephalostatins

Answer 36

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.

Question 37

Examples of some of the well-known compounds from plants that display anti-cancer properties.

Answer 37

mistletoe (Viscum album) produces proteins that interact with ribosomes deactivating them and thus displaying anticancer activity.