History of cancer chemotherapy Flashcards
What contributions did William Coley make to early cancer treatment?
He was a cancer surgeon who found records of patients with acute infections who sometimes had spontaneous cure
In 1893 he used a mixture of gram positive and negative bacteria for cancer treatment and noted success in some cases particularly those of sarcomas and lymphomas
Acute inflammation appears to play a role in this success
What progress did George Beatson make in cancer treatment?
In the 19th century he noted that patients with metastatic breast cancer often went into remission following menopause, in 1896 he removed the ovaries from a patient with breast cancer causing remission of the cancer, eventually estrogen was identified as the hormone responsible for causing the growth of hormone dependent breast cnacer
Led to the development of anti-estrogen drugs such as tamoxifen
How were alkylating agents developed?
Mustard gas development in the First world war led to cases of lymphoid hyperplasia and myelosuppression
In 1942 Goodman and Gilman tria of nitrogen mustard led to a temporary remission in lymphoma
There was then the discover that mustards cause alkylation of DNA
This later resulted in the development of clinical agents chlorambucil and cyclophosphamide in the 1950’s
How have anti-metabolites been developed?
Sidney Farber was a pathologist with an interest in childhood leukaemia who identified that folic acid increased the growth of leukaemia cells
In 9148 he developed a folic acid antagonist, aminopterin which was active against acute leukaemia
Methotrexate was subsequently developed as an analogue used for a variety of tumours such as breast cancer
The target was found to be the enzyme dihydrofolate reductase
There was also development of nucleic acid analogues as bioth anticancer and antiviral drugs with thioguanine and 6-mercaptopurine found to inhibit DNA synthesis and be useful in leukaemia treatment
5FU was then found to be useful in solid tumours
This was followed by the cytosine analogues arabinoside for leukaemia and gemcitabine for solid tumours
What are the different antibiotics which have been found to have useful cytotoxic activity?
Actinomycin D which is active in solid childhood tumours
Daunorubicin for lymphoid and myeloid leukaemias (though had toxicity issues)
Doxorubicin which was produced by mutating daunorubicin and is active in solid tumours particularly breast cancer
Mitomycin C, belomycin and other drugs have also been found to have activity
What is Vinca alkaloids?
This is a cytotoxic drug which has been developed from periwinkle plants, it was first used as a potential diabetes treatment but was found to have bone marrow toxicity
Two of the extracted alkaloids were later found to have activity in leukaemia and lymphoma and it was later found that these could bind to tubulin disrupting microtubule formation
What plant products other than Vinca alkaloids have lead to cytotoxic drug development?
Mandrake roots which provide a series of toxins one of which can produce etoposide for use in solid tumours
Camptotheca which provides camptothecin which is active but highly toxic so it was modified into irinotecan and toptecan which are used in solid tumours
The yew tree provides paclitaxel and the semi-synthetic docetaxel
What are the synthetic compounds that have been used as cytotoxic drugs?
Cisplatin and carboplatin are metallo-organic compounds discovered by chance which have wide spectrum anticancer activity
Many other DNA reactive compounds have been developed
What are the different forms of cancer models?
Transplantable tumours and human xenografts
Cell culture
US National Cancer institute testing programme
How are nude mice and human tumour cells used in anticancer drug discovery?
In the 1960s the nude mouse was discovered Glasgow this lacked a thymus meaning it produced no T cells
In 1970s human tumours growing as xenographs in the nude mice were accepted as the key model for anticancer drug development
These are still the mainstay of preclinical drug development
How is cell culture used in drug discovery?
There was concern over using mouse tumours for drug discovery as they may be lacking important targets for human cancers, they were expensive to use and had ethical concerns
In the 1980’s many human cancer cell lines became available and the development of the 96 and 384 well plate allowed for screening of large numbers of drugs
What is an example of an anticancer drug being developed through use of a unique molecular target?
Chronic myeloid leukaemia is characterized by the presence of a specific chromosomal change which results in the formation of the Philadelphia chromosome which generates the novel BCR-ABL gene which inhibits apoptosis
Gilvec was designed to fit into this protein like a glove and has the advantage of having a completely selective target
What are drugs that select for protein kinases?
Iressa
Tarceva
Staurosporine
What is Iressa?
This is a drug which inhibits tyrosine kinase activity of EGFR
What is Herceptin/transtuzumab?
The viability of tumour cells is maintained by a number of protein factors which are secreted by the surrounding stromal cells such as EGF which promote cell growth and survival
EGF binds to EGFR which forms hetero and homodimers with other members of the EGFR family including HER2
20-30% of breast cancer patients express relatively high amounts of HER2
Herceptin is a monoclonal antibody that binds to HER2 and prevents the action of the receptor this combined with cytotoxic agents can produce a killer therapy
