L9: CHEMOTHERAPY AND DRUG RESISTANCE [11/10/2022]
I. CONVENTIONAL CANCER TREATMENT
Surgery: complete removal of tumour, and cure possible if it has remained local
Radiotherapy: multiple aspects – elimination of any residual cancer cells following surgery
(adjuvant therapy); pre-operatively (neo-adjuvant); as primary therapy; palliative
Chemotherapy: cancers that have metastasized require systemic therapies
Immunotherapy
II. ‘THERAPEUTIC WINDOW’
Therapeutic window also called “therapeutic index” is the difference between the minimum
effective dose and the maximum tolerated dose (MTD)
Ideally this should be broad
III. CONVENTIONAL CHEMOTHERAPIES – 3 TYPES
1. Alkylating agents and platinum-based drugs
(eg cyclophosphamide; cisplatin, carboplatin – all form bulky DNA adducts)
2. Antimetabolites
(eg 5-Fluorouracil (5-FU) – inhibits thymidylate synthase; methotrexate – inhibits
dihydrofolate reductase)
3. Organic drugs
(eg Dexorubicin – inhibits topoisomerase II;
Vincristine – prevents microtubule assembly;
Paclitaxel (Taxol) – blocks microtubule depolymerisation)
IV. CONVENTIONAL THERAPIES – CISPLATIN
(Cancer Therapy & DNA Damage)
Many cancer therapies work by causing DNA damage – incl. ionising radiation and alkylating
agents (e.g. cisplatin)
Known for many years that these therapies affect all dividing cells
Cells cannot repair such large amounts of genomic damage, so they undergo apoptosis, or if
cancer cells lack proper cell cycle checkpoint controls, they enter “mitotic catastrophe”
(Mode of Actin)
Cisplatin is administered intravenously
Upon entering the cell [Cl-] is low (~4 mM), so the Cl- ligands are removed, generating a
positively charged species that reacts with nucleophilic sites on intracellular macromolecules
to form protein, RNA and DNA adducts.
, (Potential Problems)
Deficient DNA repair systems cause some cancers => potential problems with therapies that
work by inducing DNA damage and apoptosis
- The “therapy” may not induce a response in such cancerous cells and will not lead to
apoptosis
- It would, however, lead to apoptosis of “healthy” cells
This can enable tumours to have resistance to drugs, leading to an increase in proportion of
cancerous cells
The treatments themselves are mutagenic, so even if they eliminate the initial cancer, they
can give rise to further tumours later
(Cisplatin Resistance)
Postulated mechanisms of resistance to cisplatin:
- Reduced intracellular accumulation (↓ uptake or ↑ efflux) or increased inactivation by
intracellular proteins (e.g. glutathione)
- Increased repair of cisplatin adducts
- Increased ability to replicate past cisplatin adducts
- Defects in apoptotic response pathway
(Antimetabolites and Organic Drugs)
Actions of 5-fluorouracil (5-FU) and methotrexate
I. CONVENTIONAL CANCER TREATMENT
Surgery: complete removal of tumour, and cure possible if it has remained local
Radiotherapy: multiple aspects – elimination of any residual cancer cells following surgery
(adjuvant therapy); pre-operatively (neo-adjuvant); as primary therapy; palliative
Chemotherapy: cancers that have metastasized require systemic therapies
Immunotherapy
II. ‘THERAPEUTIC WINDOW’
Therapeutic window also called “therapeutic index” is the difference between the minimum
effective dose and the maximum tolerated dose (MTD)
Ideally this should be broad
III. CONVENTIONAL CHEMOTHERAPIES – 3 TYPES
1. Alkylating agents and platinum-based drugs
(eg cyclophosphamide; cisplatin, carboplatin – all form bulky DNA adducts)
2. Antimetabolites
(eg 5-Fluorouracil (5-FU) – inhibits thymidylate synthase; methotrexate – inhibits
dihydrofolate reductase)
3. Organic drugs
(eg Dexorubicin – inhibits topoisomerase II;
Vincristine – prevents microtubule assembly;
Paclitaxel (Taxol) – blocks microtubule depolymerisation)
IV. CONVENTIONAL THERAPIES – CISPLATIN
(Cancer Therapy & DNA Damage)
Many cancer therapies work by causing DNA damage – incl. ionising radiation and alkylating
agents (e.g. cisplatin)
Known for many years that these therapies affect all dividing cells
Cells cannot repair such large amounts of genomic damage, so they undergo apoptosis, or if
cancer cells lack proper cell cycle checkpoint controls, they enter “mitotic catastrophe”
(Mode of Actin)
Cisplatin is administered intravenously
Upon entering the cell [Cl-] is low (~4 mM), so the Cl- ligands are removed, generating a
positively charged species that reacts with nucleophilic sites on intracellular macromolecules
to form protein, RNA and DNA adducts.
, (Potential Problems)
Deficient DNA repair systems cause some cancers => potential problems with therapies that
work by inducing DNA damage and apoptosis
- The “therapy” may not induce a response in such cancerous cells and will not lead to
apoptosis
- It would, however, lead to apoptosis of “healthy” cells
This can enable tumours to have resistance to drugs, leading to an increase in proportion of
cancerous cells
The treatments themselves are mutagenic, so even if they eliminate the initial cancer, they
can give rise to further tumours later
(Cisplatin Resistance)
Postulated mechanisms of resistance to cisplatin:
- Reduced intracellular accumulation (↓ uptake or ↑ efflux) or increased inactivation by
intracellular proteins (e.g. glutathione)
- Increased repair of cisplatin adducts
- Increased ability to replicate past cisplatin adducts
- Defects in apoptotic response pathway
(Antimetabolites and Organic Drugs)
Actions of 5-fluorouracil (5-FU) and methotrexate
