Block 9 Week 6 Flashcards
Cell Cycle dependent Drug targets
- target the cell cycele
Cell cycle independent drug targets
Acute myeloid lymphoma
- Everything from myeloid lineage. Can be to do with megakaryocytes, Basophils, neutrophils …..
- E.g. Acute megakaryoblastic leukemia
- Acute myeloid leukemia - more aggressive form of the disease.
- Hematopoietic disorders (aplastic anemia, myeloproliferative disorders) or chronic myeloid leukemia can become AML.
- Crowding of blastic cells: because we are producing more wbcs we end up producing less of otehr blood cells eg. less red blood cells
- Use blood (hematogenous spread) to get to the organs around the body
-CML has the greatest potential to transform into AML of all the myeloproliferative disorders due to a mutation in a myeloid stem cell.
AML presentation
- older age patients (65 years of age)
- anemia
- neutropenia (low number of wbc) - less of other types of WBC like T-cells, B-cells, neutrophils. So the once specific WBC which has the cancer you will produce lots of but the other wbcs you produce less of because of overcrwoding.
This is why you blood count can show as high in AML.
- Thrombocytopenia: presents as epistaxis, gingival bleeding, petechia
- Leukostasis - so many extra WBC the blood gets so thick. Emergency scenario can cause pulmonary and neurologic distress.
- Leukemia cutis - purple/blue nodules ( from blastic cells infiltrating skin)
Chronic myeloid leukemia
- Chronic form less aggressive
- In AML you will see high levels of myelobalsts
- In CML you’ll see more mature cells. E.g. Promyelocytes, Myelocytes …
- t(9:22) translocation of Philadelphia chromosome. Fusion gene - BCR-ABL- between chromosome 9 and 22. This gene causes increased enzymatic activity of non-receptor tyrosine kinase. ( growth, profileration). This is why we use tyrosine kinase inhibitors treat CML
CML
- you can be in the chronic phase of myeloid leukemia for over 10 years. The suddenly you can get accelerated symptoms:
- splenomegaly
- anemia
- neutropenia
Eventually we get into blastic crisis -> AML
- can get progression to acute leukemia
-Blast crisis - forming more immature cells like myeloblast
CML presentation
- older age (50-60 yrs of age)
Elevated levels of which cells are most expected in chronic myeloid leukemia?
Answer: Metamyelocytes
Which of the following lab findings is most consistent with a patient with chronic myeloid leukemia ?
Which of the following is the primary mechanism of action of chemotherapeutics used in chronic myeloid leukemia?
Acute Lymphoblastic Leukemia
- Lymphoid stem cell - which become B-cells and T-cells
- ALL and CLL tend to be B-cell variants
- ALL more associated with the blastic cells (immature)
-
ALL presentation
- classically presents in children (2-5yrs)
- Lymphadenopathy (classic in ALL, CLL or Lymphoma). Swollen lymph nodes with no pain
- anemia
- nutropenia ( even tho WBC count high same reason as before)
- hepatosplenomegaly
Chronic Lymphocytic leukemia
- very low grade, slow rate of progression
- BCL-2 overexpression. BCL-2 prevents cytochrome c release from the mitochondria. Therefore less caspase activity -> inhibit apoptosis
- Richter transformation: having CCL can accelerate into a lymphoma. Classic one Diffuse large B-cell lymphoma
Classic presentation of CLL
- Older age 70 years of age
- Lymphadenopathy
- Features of anemia
- Features of neutropenia
- Features of thrombocytopenia
The 6 hall marks of cancer
- Resisting cell death
- Sustaining proliferative signaling
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immorality
- Inducing angiogenesis
Breast cancer
- uncontrolled growth of epithelial cells in the breast
- Hormones bind to receptors in glandular tissue which makes the alveolar cells divide and increase in number which makes the lobule enlarge.
- Without these hormones, glandular cells cant survive and undergo apoptosis
Mutations in tumor suppressor genes can cause breast cancer
- Mutations in BRCA-1 and BRCA-2 (autosomal dominant)
- Mutations in TP53
- Some people have mutations in the ERBB2 gene, which increase the Human Epidermal Growth Factor Receptor 2 ( HER-2). When activated promotes teh growth of cells
Once mutations occur:
2 types of tumors in situ
1. DCIS (ductal cell carcinoma in situ)
- LCIS (lobular carcinoma in situ)
- Ductal carcinoma In- Situ ( DCIS) :
- tumor cells grow from the wall of the ducts into the lumen
- if left untreated -> cancer cells can cross the basement membrane -> invasive ductal cell carcinoma
- Cancer cells can migrate to the nipple, causing ‘pagets disease’ of the nipple
LCIS (lobular carcinoma in situ)
- Clusters of tumor cells grow within the lobules, without invading the ducts causing the affected alveoli to enlarge.
- Doesn’t cross the basement membrane to form invasive lobular carcinoma
Breast cancers divided into 3 major types:
- Estrogen receptor (ER) positive & HER-2 negative carcinoma
- HER2-Positive & ER- Positive/negative carcinoma
- ER- negative & HER2- Negative carcinoma
Symptoms of breast cancer
Diagnosis
Treatment
Colorectal cancer
- malignant or cancerous cells arise in the large intestine and colon and rectum
- walls of G.I. tract are made up of 4 layers.
Outermost:
-serosa (intraperitoneal parts)
-adventitia (retroperitoneal parts) - muscular layer
- submucosa
- inner layer (mucosa) surrounds the lumen of the G.I. tract and comes in direct contact with digestive food.
Mucosa has invaginations:
- intestinal glands
- colonic crypts
- Most colorectal carcinomas are adenocarcinomas - meaning they arise from the cells lining the intestinal glands
Colorectal cancer mutations
- Most due to sporadic mutations, however some are due to known mutations
- For example APC gene ( Adenomatous Polyposis Coli Gene) which is a tumor suppresor gene. Normally APC gene identifies when a cell is accumulating a lot of mutations and forces it to undergo apoptosis.
- If APC gene (tumor suppressor gene) is mutated, its not gonna halt the cell cycle and we are going to get uncontrolled cell division, which gives rise to POLYPS
- Over time these polyps may accumulate more mutations like in the p53 gene or K-RAS gene and become a malignant tumor which may invade neighboring tissues.
- Another well known example are genetic mutations in DNA repair genes which help fix up mutations in cellular DNA.
-When they’re out of action - cells accumulate mutations and over time can develop into polyps and eventually adenocarcinomas.
-So, broadly speaking, adenocarcinomas are the malignant evolution of polyps, and polyps arise when cells start dividing faster than usual.
Types of polyps
- There are many different types of polyps are some are more prone to becoming malignant, they are called pre-malignant or neoplastic polyps
These polyps can become:
1. Adenomatous
2. Serrated
Stages of cancer
Risk factors
Symptoms of collorectal cancer
Diagnosis:
Barium Enema:
- liquid injected into the rectum through a small tube and x ray is taken to look for abnormalities in the large intestines.
- On a barium enema a classic sign of colorectal cancer is the ‘apple-core sign’
Treatment for colorectal cancer
CARCINOGENESIS
5 hallmarks of cancer development:
- sustaining proliferative signaling
- resisting cell death
- introducing angiogenesis
- enabling replicative immorality
- activating invasion and metastasis
- evade growth suppressors
- avoid immune destruction: tumor cells have developed ways to avoid recognition and immune cell mediated killing.
- tumor-promoting inflammation
- deregulated cellular energetics - there is a difference in the metabolism of cancer cells compared to healthy cells. Cancer cells have different glycolytic activity in comparison to normal cells.
DNA damage
- P53, p21 business
- ATM or ATR are activated and this inturn induces the activation of checkpoint molecules.
- Checkpoint molecules; main job to control and regulate the cell cycle
- upon the activation of ATM and ATR kinases we have accumulation of the protein p53 that we discussed previously.
- p53 (guardian of genome) - regulates tightly cell cycle.
Types of DNA damage
UV light
Alkylating agents
Endogenous - Biotransformation
Aflatoxin
ATM
- ATM comes from a rare genetic syndrome. In this syndrome there is defective function of cell cycle checkpoints in response to DNA damage.
- particularly we talk about double stranded breaks in this case. ATR comes from 80 related.
p53 mutations exogenous and endogenous
Repair of alkylation damage
- DR
- BER
NER
Xeroderma Pigmentation (XP)
Double strand break repair (DSB)
Non homologous end joining
Homologous recombination
Cancer genes
-Mutations in tumor suppressor genes, DNA repair genes and oncogenes can all cause cancer
- point mutations
Tumor supressor genes
Inherited predisposition to cancer
Colorectal cancer
HNPCC: Defective mismatch repair
Gatekeeper and caretakers
TREATMENT OF CANCER
Grade:
- The more abnormal the cells look and organize themselves, the higher the cancer’s grade
- Lower grade cancers are typically less aggressive and have a better prognosis
Stage:
- how the cancer has behaved already. how far its gone and how big its got.
Most common TNM
Diagnosing cancer
CASE STUDY
- no abnormalities on blood test
- chest x ray
- radical treatment
google it then go through case studies
