Lecture 8 - Intro To Chemotherapy Flashcards
Different treatments for cancer
- treating the complications
- cytotoxic therapy
- local therapies
- endocrine therapy
- immunotherapy
- enzyme inhibitors
- molecular therapy
- supportive care
Goals of systemic therapy
- curative
- debulking before surgery
- adjuvant
- radioenhancing
- prolong survival
- palliative
Chemotherapy
- nitogen-mustard discovered during chemical warfare research
- development of chemotherapy since mostly a result of empiricism
The ideal cytotoxic
- would exploit unique property of tumour cells, thus providing tumour specific therapy
- no such pure cytotoxic drug exists
- collateral damage limits the effectiveness of systemic chemotherapy
- autoloytic stem cell rescue allows you to give high dose chemotherapy before trasnplant - hematopoiesis resues
Spectrum of chemosensitivity
- Drug resistant to curable: renal cancer, pancreas - colon - breast - ovarian lymphoma - germ cells
Cell cycle
- cells with moderate amounts of DNA damage are arrested in G1
- after DNA repair, the cell cycle resumes
P53: maintenance of fidelity
- gives rise to P21 -> CDK4 -> cell cycle arrest, DNA repair
- Apaf 1 -> caspases -> cleavage of vital molecules -> apoptosis
Killer molecules: Bax, Bak, Bad, Bim -> promote p53 pathway
Prosurvival molecules: Bcl2, Bcl3, BCl w molecule -> inhibit p53 pathway
How does a cell become malignant
- increase activitiy of positive growht signals (activation of proto-oncogenes)
- decrease activity of negatively acting growth signals: loss of tumour suppressor gene function (eg: P53)
- decrease in the pathways leading to PCD
Conventional chemotherapy 5 main classes
- alkylating agents: cross links DNA. Eg: cyclophosphamide
- antitumour antibitotics: intercalate DNA base pairs (Daunorubicin), breaks DNA (Bleomycin)
- platinum compounds: crosslink DNA (Cisplatin, Carboplatin)
- anti-metabolites: Methotrexate (an anti-folate), 5FU, Ara-C… Competitive inhibitors of S phase enzymes
- anti-microtubule drugs: taxanes and vincristine: bind microtubular proteins disrupting microtubule assembly during mitosis. Inhibition of the mitotic spindle leads to arrest in G2/M
Alkylating agents: classic cytotoxic
- add alkyl groups to intracellular DNA/cross linking interferes with DNA synthesis
- non-selective, toxicity to all rapidly dividing cells
- eg: cyclophosphamide
- side effects: anorexia, alopecia, amenorrhea, azoospermia, mutagenic, myelosuppressive (marrow suppression), immunosuppressive (AAAMMI). Nausea + vomiting
Combination chemotherapy 4 princiuples
- drugs active as single agents should be selected
- drugs with different MOA
- drugs with different dose limiting toxicities
- drugs with different susceptibilities to resistance
- generally aim for max dose with minimum time interval between doses (2-3 weeks for recovery)
Multiagent chemotherapy: MOPP
- Mustine
- Oncovine
- Procarbazine
- Prednisolone
- Hodgkin lymphoma
Multiagent chemotherapy: CMF
- cyclophoaphamide, methotrexate, 5Fluorouracil
- for breast cancer
Mjultiagent chemotherapy: CHOP
- Cyclophosphamide, H-adriamycin, Oncovin, Vincristine, Prednisone
- for non-hodgkin lymphoma
- R-CHOP: add rituximab
Assume all cytotoxics cause
- anorexia, nausea, vomiting
- alopecia
- myelosuppression
- gonadal damage
- immune suppression
Which drugs dont cause hair loss
- carboplatin, 5FU, vincristine, mitoxantrone
Which cytotoxics dont damage the marrow
- bleomycin
- vincristine
- cisplatin
- 5FU
Unite toxicities
- Doxorubicin, idarubicin - cardiac toxicity
- Bleomycin - lung toxicity
- Vinca alkaloids - peripheral neuropathy
- cyclophosphamide - haemorrhagic cystitis
- Cysplatin - kidney toxicity
Supportive care
- pre treatment: counselling, education, teeth, fertility, nutrition
- with treatment: anti-emetics (5HT3 receptor antagonist, aprepitant)
- post treatment: anti-emetics, laxatives, g-CSF, autologous stem reinfusion, iv fluids, folinic acid after MTX
Drug targets unique to cancer cell are rare but do exist
- BCR–ABL in CML: blocked by imatinib and other tyrosine kinase inhibitors
- PML/RAR in APML: differentiation therapy: ATRA: a vitamin A analogue lifts the block in myeloid differentiation
Rituximab
- anti-CD20 in B NHL
- 15% increase in response and survival rates
Trastuzumab (herceptin
- blocks the HEr2 receptor protein expressed in breast cande - increased survival when added to chemotherapy
Monoclonal antibodies: Bevacizumab
- inhibits VEGF: a protein that stimulates angiogenesis - new vessel formation
- benefit in metastatic colon cancer
- monoclonal antibodies: brentuximab
- anti-cd30 in T-NHL and HL
Ipilimumab
- blocks the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on lymphocytes
- blocking this immune checkpoint inhibitor allows CTL to destroy the melanoma cells
- immune mediated side effects
- PBS approved
Vemurafenib - small molecule inhibitor
- V600E mutated BRAF inhibitor present in 50% of melanomas
- 600 patient trials
- TGA approved, not PBS listed
- photosensitive
Other immuno-modulatory cancer therapies
- replacing/complementing traditional chemotherapied in myeloma
- thalidomide and lenalidomide
- bortezomib inhibits the proteasome proteins the myeloma cells need for homeastis
- multiple MOA: direct anti-tumour effect, induign apoptosis, anti-angiogenic, immune modulatory
B cell enzyme inhibitors
- BCR signalling blockade by ibrutinib: imhibitor of Bruton’s TK in relapse CLL, mantle cell lymphoma, waldenstrom