Lecture 17 - Treatment-related late effects

What are the biological effects of ionising radiation on cells?

• DNA strand breaks 

• H2O conversion into H2O+ and e- 

  • H2O+ is a ROS which can dissociate to produce OH- OR react with water to produce H3O+ and OH-

What are alkylating agents?

Reactive compounds which can donate an alkyl group to other molecules 

• Methylation of nucleotides is the primary mechanism of toxicity

What is a methylating agent?

Reactive compound which donates CH3 to other molecules.

What is an ethylating agent?

Reactive compound which donates CH2H5 to other molecules.

What is a chloromethylating agent?

Reactive compound which donates CH2Cl to other molecules.

Alkylating agents can broadly be grouped based on the number of reactive groups. These two groups are:

• Monofunctional 

  • Only reacts with one strand of DNA 

• Bifunctional  

  • Can react with two strands of DNA 

    • This allows formation of cross-links between two strands of DNA 

Why does methylation of nucleotides result in cell toxicity?

The methylated nucleotides behave very differently

• O6-methylguanine has very different biological effects to guanine  

What are Topoisomerase inhibitors?

Topoisomerases are important enzymes responsible for cleaving the DNA 

• Inhibitors interfere with the enzymes and result in the formation of protein-capped DNA double strand breaks

What is type 1 topoisomerase enzyme?

• Type I – Cleave single DNA strand 

  • Allows for strand unwinding and torsion release  

What is type 2 topoisomerase enzyme?

• Type II – Cleave double DNA strand 

  • Allows for untangling of DNA strands 

How do topoisomerase inhibitors result in cell toxicity?

• Inhibitors can result in formation of a protein-capped DNA double strand break

  •  Traps the enzyme on the DNA causing breaks

  • This is recognised by the cell, and this either results in cell death or a mutation if the cell tries to repair it 

Why are anti-cancer agents toxic and mutagenic to healthy cells?

• Majority of chemotherapy disrupt DNA replication/cell division

  • These target cells with high rate of proliferation such as cancer but also healthy fast growing cells

    • Causes loss of hair follicles, GI mucosa and B/T lymphocytes 

    • Immediate effects as a result of acute toxicity 

What are the long term effects of Cisplatin, Bleomycin and Radiation?

• Infertility 

• Cognitive impairment 

• Hypogonadism (Impaired function of gonads – low testosterone)  

  • Premature ageing  

  • Type II diabetes  

  • Cardiovascular disease 

• Pulmonary toxicity  

• Nephrotoxicity

  • Kidneys 

• Ototoxicity

  • Ears  

What socioeconomic effects does cytotoxic cancer therapy have?

• Low social engagement 

• High unemployment 

• Sedentary lifestyle  

• Depression and Anxiety  

What is an example of a life threatening late effect of cancer therapy?

Myocytic vacuoles

• Clear areas which are void of cardiac myocyte fibres  

• Ultimately causes an increased risk of heart failure  

What cancer therapy can cause myocytic vacuoles?

Anthracyclines (Doxorubicin and Daunorubicin) 

• Targets cardiac myocytes  

• Reaction with iron causes production of ROS 

  • Apoptosis 

  • Cardiac fibrosis 

How do Anthracyclines work?

Topoisomerase II inhibitors

• Causes lethal double-strand DNA breaks

Can also intercalate into DNA and generate ROS leading to apoptosis

• Recent studies also suggest they can cause the loss of histones resulting in DNA damage

What is treatment related cancer?

• Cancer which develops because of therapy for a primary cancer 

The biggest single cause of death in long-term Hodgkin Lymphoma survivors is…

• Second cancer is the biggest single cause of death in long-term Hodgkin Lymphoma survivors  

  • Most known chemotherapy regiments and radiotherapy are known or suspected human carcinogens  

    • E.g. MOPP and ABVD

Secondary cancer development due to treatment is equally likely to cause cancer in any tissue in the body.

True or False?

False.

• Tissues can differ in their relative sensitivity to the carcinogenic effects of treatment 

  • E.g. Colon and breast cancer are relatively less common compared to acute myeloid leukaemia (AML) 

How can topoisomerase inhibitors result in cancer development?

• Hint: Secondary leukaemia

• Can target the mixed lineage leukaemia (MLL) gene which is associated with secondary leukaemia  

• Can cause cleavage near the gene resulting in MLL translocation onto other chromosomes 

• MLL gene encodes a large protein which functions as a histone methyltransferase 

  • Allows it to regulate transcription 

• Translocation can result in fusion gene production which can produce oncofusion proteins which aberrantly upregulate transcription of genes involved in cell proliferation  

How can alkylating agents induce leukaemia?

• Addition of methyl group to O6 of guanine can produce O6-methylguanine  

• This molecule is highly mutagenic 

  • Can align with T rather than C due to its O6 oxygen no longer being able to produce hydrogen bonds  

  • This can introduce a point mutation 

Why is bone marrow more susceptible to transformation by alkylating agents?

• Relatively little Methylguanine Methyltransferase (MGMT) compared to DNA within myeloid precursors 

  • MGMT is involved in repair of O6-methylguanine back into guanine

  • Suggests bone marrow is more susceptible to alkylating agents due to low levels of DNA repair proteins like MGMT 

How is radiotherapy able to induce cancer development?

• Radiotherapy cause DNA damage in some cells 

• An initial failure to repair the damage or apoptose the cell results in the DNA damage being fixed as a mutation in rapidly dividing cells 

• These rapidly dividing cells could then transform 

• This then leads to rapid clonal expansion which leads to cancer development 

In the case of breast cancer, what has been shown to be protective against radiogenic cancer?

• Evidence suggests that chemotherapy can protect against radiogenic breast cancer 

  • Radiotherapy alone conferred a greater risk of breast cancer than radiotherapy and chemotherapy combined 

Why is it thought that chemotherapy can protect against radiogenic breast cancer?

• Thought that the chemotherapy is impacting oestrogen function in the ovaries which reduces proliferation of developing breast cancer

• This helps protect against radiogenic breast cancer development

In the case of breast cancer, what has been shown to increase the risk of radiogenic cancer?

• Oestrogen has been shown to increase the risk of radiogenic breast cancer. 

How does age at exposure to cancer treatment impact on acute myeloid leukaemia development?

• For acute myeloid leukaemia, age has a limited impact on relative risk 

  • Risk drops with increasing age, but risk remains high throughout life 

How does age at exposure to cancer treatment impact on breast/thyroid cancer development?

• For breast/thyroid cancer, the risk is very high early on in life (<21) 

Why is it thought that younger women are more at risk of secondary breast cancer development due to cancer therapy?

• When young women’s breast tissue is developing, cell division rate is very high 

• Exposing these cells to cancer treatment increases the risk of transforming the tissue 

  • Generates DNA damage  

• Once the breasts stop developing, the cells have more time to repair damage and can better avoid transforming  

When treating Hodgkin’s Lymphoma, what treatment related effect can occur in males?

• Males 

  • Susceptible to gonadal toxicity from alkylating agent chemotherapy  

When treating Hodgkin’s Lymphoma, what treatment related effect can occur in females?

• Females 

  • Substantial risk of breast cancer after chest radiation  

What are examples of cancers which Imatinib is used to treat?

• Chronic myeloid leukaemia (CML) and Acute Lymphoblastic Leukaemia (ALL)

  • Which are Ph chromosome positive

What is Rituximab used to treat?

• B-cell Lymphomas

  • Targets CD20 and causes ADCC, CDC and apoptosis

What is Iplimumab used to treat?

• Lymphomas

  • Anti-CTLA-4 antibody which prevents T-cell inhibition

What is Rucaparib used to treat?

• Breast, ovarian and prostate cancer

  • Inhibitor of PARP enzymes, blocking single-strand DNA break repair

  • Effective in BRCA-deficient cancer

Current data about newer targeted therapies seems to suggest they are just as likely to transform healthy tissue and cause secondary cancers.

True or False?

False.

• Current data seems to suggest that these therapies are much less likely to transform healthy tissue