CELL CYCLE AND CANCER CHEMOTHERAPY Flashcards
Cancers occur through the following 6 mechanisms
- Epigenetic alteration
- Alterations in genes that stimulate cellular growth
- Mutation of G-protein coupled receptors (GPCRs).
- Loss of tumor suppressor gene function
- Loss of cell death
- Stimulation of apoptosis in immune cells
% of HPV infections that transform to cervical cancer
1%
Addition of chromosomes — and —- and the loss of chromosomes 2q, 3p and 11q have been detected in patients with cervical cancer
1q
3q
Addition of chromosomes 1q and 3q and the loss of chromosomes —, — and —- have been detected in patients with cervical cancer
2q, 3p and 11q
The gene located in chromosome 3q whose expression is frequently in cervical cancer
Fragile histidine triad gene (FHIT)
The fragile histidine triad gene (FHIT) is located on which chromosome
3q
T/F: FHIT (fragile histidine triad gene) expression is frequently increased in cervical cancer
F.
Reduced
T/F: Over expression of p16 and c-myc are detected in early events in cervical cancer
T
Over expression of — and — are detected in early events in cervical cancer
p16 and c-myc
Mutations in the —or — genes are suggested to be a late event for cervical carcinogenesis
K-RAS or H-RAS
T/F: Mutations in the K-RAS or H-RAS genes are suggested to be an early event for cervical carcinogenesis
F
Late event
T/F: The receptor-binding cancer antigen (RCAS1) is also expressed among cervical cancer patients.
T
T/F: Cellular transformation could also be associated with the integration of HPV DNA into the host genome
T
— and — bind to and inactivate p53 and Rb, respectively, resulting in transformation of cervical epithelial cells
E6 and E7
p53 is bound and inactivated by —
E6
Rb is bound and inactivated by —
E7
Types of endometrial cancer according to clinicopathological variables
Type l and Type ll
T/F: Type I endometrial cancer arises from preneoplastic lesion hyperplasia that has undergone unchecked estrogenic stimulation
T
—, — and — are suggested to be early events in endometrial carcinogenesis
- Loss of PTEN (phosphatase and tensin homologue) expression
- K-RAS mutation
- MSI (microsatellite instability)
Type II carcinomas develop from –
Atrophic endometrium
T/F: Type ll endometrial carcinomas are frequently serous or clear cell adenocarcinomas
T
— mutations occur in ~90% of serous adenocarcinomas
TP53 mutations
P16 inactivation, HER2 overexpression and reduced E-cadherin expression are observed in ~—, — and —% of cases, respectively
P16 inactivation = 45%
HER2 overexpression = 70%
Reduced E-cadherin expression in 80%
T/F: RCAS1 expression is increased in endometrial adenocarcinoma
T
Serous borderline tumor and low-grade serous adenocarcinoma of the ovaries are due to mutations in — and —
K-RAS and BRAF
T/F: Ovarian cancer has frequent mutations in TP53 and occasional over expression of HER-2/neu, AKT2 and MYC
T
Endometrioid and clear cell adenocarcinomas of the ovary are associaed with mutations of — and —
PTEN and PIK3CA
Mucinous adenocarcinoma of the ovary is associated with mutations in —
K-RAS
% of ovarian cancers attributable to inherited mutations of cancer susceptibility genes, including BRCA1 and BRCA2
10%
—, — and —have been reported to play pivotal roles in proliferation and dissemination of ovarian cancer.
- Lysophosphatidic acid
- Heparin-binding EGF (HB-EGF)
- Amphiregulin
The most commonly mutated gene HPV negative vulva cancer
TP53
In HPV negative vulva cancer there is addition of — and — chromosomes
7p and 8q
In HPV negative vulva cancer there is loss of — chromosomes
2q
T/F: HPV-negative ( − ) vulvar cancer contained one or more somatic mutations in TP53, CDKN2A, HRAS, KRAS, PIK3CA, PPP2R1A and PTEN
T
HPV-positive (+) vulvar cancer has a TP53 mutation in —% of cases
17%
In HPV positive vulva cancer there is addition of the — chromosome
3q
In HPV positive vulva cancer there is loss of the — chromosome
11q
For vaginal cancer HPV secretes — and — proteins
E6 and E7 proteins
In vaginal cancer E6 proteins cause — mutation
TP53
In vaginal cancer E7 proteins cause mutation
Rb
4 clinical applications of molecular basis of gynaecologic cancers
- Prevention of gynaecologic cancers
- Early detection and prompt treatment
- Determination of appropriate treatment options
- Monitoring
The 5 phases of the cell cycle
G0, G1, S, G2 and M
Define cell cycle
This is a series of steps that both normal cells and cancer cells go through in order to form new cells
G0 phase (resting stage):
The cell has not yet started dividing. Depending on the type of cell, G0 can last from a few hours to a few years
G1 phase:
The cell starts making more proteins and growing larger. This phase lasts about 18 to 30 hours.
Duration of G0
A few hours to a few years depending on cell type
Duration of G1
18 to 30 hours
S phase:
The chromosomes containing the genetic code (DNA) are copied so that both of the new cells formed will have matching strands of DNA. This phase lasts about 18 to 20 hours
Duration of S phase
18 - 20 hrs
G2 phase:
The cell checks the DNA and gets ready to start splitting into 2 cells. This phase lasts from 2 to 10 hours
Duration of G2
2 to 10hrs
M phase (mitosis):
The cell actually splits into 2 new cells. This phase lasts only 30 to 60 minutes
Duration of M phase
30 to 60 minutes
The phases that make up the interphase
G1, S and G2 phases are called interphase
4 stages of mitosis
Prophase, Metaphase, Anaphase and Telophase
Define mitosis
This is a nuclear division plus cytokinesis, and produces two identical daughter cells
Chromatin in the nucleus begins to condense and becomes visible in the light microscope as chromosomes. The nucleolus disappears. Centrioles begin moving to opposite ends of the cell and fibers extend from the centromeres. Some fibers cross the cell to form the mitotic spindle
Prophase
Spindle fibers align the chromosomes along the middle of the cell nucleus
Metaphase
The paired chromosomes separate at the kinetochores and move to opposite sides of the cell.
Anaphase
: Chromatids arrive at opposite poles of cell, and new membranes form around the daughter nuclei. The chromosomes disperse and are no longer visible under the light microscope
Telophase
a fiber ring composed of a protein called actin around the center of the cell contracts pinching the cell into two daughter cells, each with one nucleus
Cytokinesis
2 goals of chemotherapy
control of cancer
Palliation of symptoms of cancer
FRACTIONAL CELL KILL HYPOTHESIS -
Each time the chemotherapy dose is repeated, the same proportion of cells not the same absolute number, is killed
3 LOG KILL, 1 LOG REGROWTH PRINCIPLE -
in a tumor with 10^10 cells, a cycle of chemotherapy will result in 10^3 (3log kill) cells dying &10^7(7log kill) Cells remaining. Hence repeated cycles are required to eradicate remaining and re–growing cells
2 classes of chemotherapeutic drugs
Cell cycle specific and cell cycle non-specific drugs
T/F: Cell cycle specific chemotherapeutic drugs have a plateau with respect to cell killing ability
T
T/F: With cell cycle specific drugs, the amount of cell kill will not increase as drug dosage increases.
T
3 groups of the cell cycle chemotherapeutic drugs
- Antimetabolites
- Vincaplant alkaloids
- Miscellaneous agents such as asparaginase and decarbazine
T/F: Cell cycle specific drugs are administered in minimal concentration through continuous dosing methods
T
T/F: cell cycle non-specific drugs can act at several or all cell cycle phases
T
T/F: Cell cycle non-specific drugs have a linear dose-response curve
T
which means that the greater the dose of drug that is given, the greater is the fraction of cells within the tumour that are killed
Which class of chemotherapeutic drugs have a linear dose-response curve
Cell cycle non-specific drugs
5 groups of cell cycle non-specific drugs
- Alkylating agents
- Antitumour antibiotics
- Nitrosureas
- Noncytotoxic drugs such as hormone and steroid drugs
- miscellaneous agents such as procarbazine
How are cell cycle non-specific drugs given
Often given as a single bolus injection
How are cell cycle specific drugs given
Cell cycle specific drugs are administered in minimal concentration through continuous dosing methods
T/F: Tumor cells in G0 phase are refractory to treatment
T
2 drugs that act on the G1 phase
L-asparaginase
Corticosteroids
4 drugs that act on the S phase
Procarbazine
Antimetabolites
Hydroxyurea
Camptothecins
3 drugs that act on the G2 phase
Bleomycin
Vinca alkaloids
Taxanes
5 drugs that act on the M phase
Vinca alkaloids
Taxanes
Podophyllotoxins
Etoposide
Teniposide
2 groups of drugs that can kill non-dividing cells
Steroids and Antitumor antibiotics
3 groups of drugs that can kill dividing cells at any point in the cell cycle
Alkylating agents
Platinum compounds
Cell–signaling inhibitors
5 indications for combination chemotherapy
- Prevention of resistant clones
- Cytotoxicity to resting & dividing cells
- Biochemical enhancement or effect
- Sanctuary access
- Rescue
10 types of chemotherapy agents
Alkylating agents
Antimetabolic agents
Antibiotic agents
Topoisomerase inhibitors
Mitotic inhibitors
Corticosteroids
Targetted therapies
Differentiating agents
Hormone therapy
Immunotherapy
Others
Mechanism of action of alkylating agents
These drugs directly damage the DNA. They affect all phases of the cell cycle
T/F: Antimetabolic agents kill cells in S phase
T
10 examples of antimetabolic agents
5-fluorouracil
6-mercaptopurine
Capecitabine
Cytarabine
Floxuridine
Fludarabine
Gemcitabine
Hydroxyurea
Methotrexate
Pemetrexed
8 examples of antibiotic chemotherapeutic agents
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Actinomycin-D
Bleomycin
Mitomycin-C
Mitoxantrone (also acts as a topoisomerase II inhibitor)
T/F: Mitoxantrone also acts as a topoisomerase II inhibitor
T
Mechanism of action of topoisomerase inhibitors
These drugs interfere with enzymes called topoisomerases, which help separate the strands of DNA so they can be copied during the S phase
Topoisomerase l and topoisomerase ll
Topoisomerase I inhibitors include: — and —
Topotecan
Irinotecan
Topoisomerase II inhibitors include: — and —
Etoposide
Teniposide
T/F: Mitoxantrone is a topoisomerase inhibito
T
Mitoxantrone (also acts as an anti-tumor antibiotic)
4 examples of mitotic inhibitors
Taxanes: paclitaxel and docetaxel
Epothilones: ixabepilone
Vinca alkaloids: vinblastine , vincristine and vinorelbine
Estramustine
3 chemotherapeutic corticosteroids
Prednisone
Methylprednisolone
Dexamethasone
4 examples of targeted chemotherapeutic drugs
Imatinib
Gefitinib
Sunitinib
Bortezomib
T/F: Targeted therapies attack cancer cells more specifically than traditional chemotherapy drugs
T
4 examples of differentiating agents
Retinoids,
Tretinoin
Bexarotene
4 Arsenic trioxide
6 groups of anticancer hormone therapy and their examples
Anti-estrogens: fulvestrant , tamoxifen, and toremifene
Aromatase inhibitors: anastrozole , exemestane and letrozole
Progestins: megestrol acetate
Estrogens
Anti-androgens: bicalutamide , flutamide and nilutamide
Gonadotropin-releasing hormone (GnRH) analogs : leuprolide and goserelin
6 classes of anticancer immunotherapy drugs
Monoclonal antibody therapy, such as rituximab and alemtuzumab, Trasluzumab, Cetuximab,
Tyrosine Kinase inhibitor-Imatinib
EGFR inhibitor-Erlotinib,Gefitinib
VEGF-Bevacizumab
Non-specific immunotherapies and adjuvants (other substances or cells that boost the immune response), such as BCG, interleukin-2 (IL-2), and interferon-alfa
Immunomodulating drugs, such as thalidomide ,lenalidomide and levamisole.
T/F: L asparaginase, which is an enzyme, and the proteosome inhibitor bortezomib are also chemotherapy drugs
T
Derived from the murine VEGF monoclonal antibody A4.6.1
Bevacizumab (Avastin)
T/F: Bevacizumab has about 93% human and 7% murine protein sequence
T
producing an agent with the same biochemical and pharmacologic properties as the parental antibody, but with reduced immunogenicity, and a longer biological half-life
T/F: Bevacizumab can be given as monotherapy or in combination therapy with other chemotherapy agents and/or radiotherapy.
T
Blocks tumor angiogenesis and growth with high potency and efficacy.
Bevacizumab
T/F: Bevacizumab Inhibits VEGF-induced proliferation of endothelial cells in vitro with ED50 of 50 ± 5 ng/mL.
T
T/F: Experimental studies show that bevacizumab neutralize all isoforms of human VEGF with a dissociation constant (Kd) of 1.1 nmol/L
T
Dosing of Bevacizumab
5-10mg/kg IV given once every 2 weeks.
7.5-15 mg/kg IV given once every 3 weeks.
Agents that sensitize the tumor cells to radiation
Radiosensitizers
Compounds that are designed to reduce the damage in normal tissues caused by radiation
Radioprotectors
Aim to interrupt or reduce the radiation-induced toxicity
Radiation mitigators
Complications of chemotherapy
GI- Nausea and Vomiting, diarrhoea
Respiratory System-Pulmonary fibrosis
Nervous system-Neuropathy
CVS-Cardiotoxicity, Phlebitis
Urinary system-Nephrotoxicity, Cystitis
Reproductive system-Sterility,
MSS-Myagia,Bone marrow suppression,
Dermal-Alopecia,Local reaction.
Hematologic-Anaemia,Leucopenia
3 ways to prevent drug resistance in chemotherapy
Reduce tumor bulk with surgery
Use combinations including drugs that affect resting population
Schedule drugs to prevent phase escape or to synchronize cell populations and increase cell kill.
8 contraindications to chemotherapy
Infection
Neutropenia
Thrombocytopenia
Severe debilitation
Pregnancy (1st trimester)
Major surgery <2 wks prior
Poor patient follow-up
Psychological problem
12 examples of radiosensitizers
- Hyperbaric oxygen
- Carbogen
- Nicotinamide
- Metronidazole and its analogs (misonidazole, etanidazole and nimorazole)
- Hypoxic cell cytotoxic agents (Mitomycin-C, Tirapazamine)
- Membrane active agents (procaine, lidocaine, prochlormazine)
- Radiosensitizing nucleosides (5-fluorouracil, fluorodeoxyuridine, bromodeoxyuridine, iododeoxyuridine, hydroxyurea, gemcitabine, fludarabine)
- Texaphyrins (motexafin gadolinium)
- Suppressors of sulfhydral groups (N-Ethylmalemide, Diamide and Diethylmaleate)
- Hyperthermia
- Novel radiosensitizers (paclitaxel, docetaxel, irinotecan)
6 radioprotectors
- Amifostine
- Nitroxides (tempol)
- Other antioxidants (glutathione, lipoic acid, Vit. A, C and E, superoxide dismutase)
- Cysteine and cysteamine
- Melatonin
- Novel radioprotectors (tetracyclines and fluoroquinolones)
6 radiation mitigators
- Palifermin
- Halofuginone
- TGF - B
- Keratinocyte growth factor
- ACE inhibitors (Captopril, enalapril, ramipril)
- COX-2 inhibitors/NSAIDs (Celecoxib, aspirin and ibuprofen)
