name the 4 phases of the cell cycle
G1 Phase
S Phase
G2 Phase
M Phase
name the 4 stages of mitosis
Prophase
Metaphase
Anaphase
Telophase
Which is the longest phase of the cell cycle, lasting about 10 hours
S Phase
What is the shortest phase of the cell cycle
M Phase (Mitosis)
these cells have receptors that determine if cells of cells they encounter are self or non-self. Their role is to destroy non-self cells
Natural Killer Cells
Mitosis phase in which Nuclear envelope has disappeared, and chromosomes move toward the cell equator. Sister chromatids have not separated. The metaphase checkpoint ensures that the chromosomes are aligned properly before separation.
Metaphase
Mitosis phase in which Centrioles move toward opposite poles, and the nuclear envelope breaks down.
Prophase
Mitosis phase in which Two sister chromatids separate into chromosomes.
Ananphase
Mitosis phase in which Nuclear envelope has disappeared, and chromosomes move toward the cell equator. Sister chromatids have not separated. A checkpoint ensures that the chromosomes are aligned properly before separation.
Metaphase
During which phase of the cell cycle does DNA replication occur
S Phase
proteins that control the cell cycle
cyclins
pluripotent stem cell
Cell capable of giving rise to any of the specialized cell types in the body.
nonspecific immunity
phagocytosis and inflammation (2nd line of defense – Also 1st line of defense skin…)
_ precursors, or “pre-cells,” mature into red blood cells (RBCs), platelets, and white blood cells (WBCs).
Myeloid
_ precursors, or “pre-cells,” mature into specialized WBCs called lymphocytes.
Lymphoid
During which phase of the cell cycle do cells enlarge and pass a checkpoint that determines the cell is ready to divide
G2 phase
During which phase of the cell cycle do cells enlarge and pass a checkpoint that determines the cell is ready to divide
G2 phase
three types of granulocytes
neutrophils, eosinophils, basophils
_, including Natural killer cells, granulocytes and macrophages are the second line of defense in the immune system (after skin, mucus membranes and gut flora)
Phagocytes
nonspecific immunity
phagocytosis and inflammation (2nd line of defense)
Learned specific immunity
3rd line of defense which includes antibodies and lymphocytes
2 types of lymphocytes
T cells and B cells
important tumor suppressor gene, sometimes called the “suicide gene.”
p53 gene
Resources
nccn.org
cancer.org
LESSON 1: Cell cycle
g1- increase in size
s- dna replicated
g2- cell enlarge and ready to divide
m phase- 2 hours
mitosis
4 stages, prophase, metaphase, anaphase, telophase
-chemo targets certain points in the process
apoptosis
programmed cell death
hematopoiesis
formation of blood cells & how cells differentiate
-myeloid: pre cells mature into RBCs, platelets and WBCs
-lymphoid: pre cells- mature into WBCS
Principles of Biotherapy: p51-95 immunology
-defense against foreign organisms, homeostasis (destroy aged cells), surveillance
immune responses
innate: primary line of defense, non specific, no memory
adaptive: secondary line of defence with specific memry
cytokines
-effect growth and differentiation of WBC
-interferons, tumor necrosis factors, growth factos and interleukins
-small protein molecules released by cells throughout body providing comunication between cells of the immune system
-regular antiboddy production and function of b cells
vaccines for cancer prevention
-hep B prevents hepatitis and hepatocellular carcinoma
-hpv vaccine
filgrastim aka neupogen
SC or IV to derease infection in patients with neutropenic fever associated with myelosuppressive anticancer treatments for nonmyeloid malignancies
tbo-filgramstim/ pegfilgrastim
reduce duration of neutroenia in patients with non myeloid malignancies
palifermin
IV to dec incidence of oral mucositis in patients with hem malignanies before BMT
sargramostim
aka leukine – patients with AML following chemo to shorten neutrophil recovery and reduce incidence of infection
IFN gamma
reduce frequency and severity o infections related to granulomatous disease
aldeleukin
treat renal cell carcinoma and metastatic melanoma
oprevelkin
prevent severe thrombocytopenia and refuce need for platelet transfusions in patients with nonmyeloid malig
plerixafor
with filgrastim to mobilize hematopoeitc stem cells for collection from peripheral blood of patients
sipuleucel
castrate resistant prostate cancer
rituximab
rituxan- treatment of relapsed or refractory low grade follicular b cell NHL_ first line traetment in combo with chemo in patients with response
-can treat severe rheumatoid arthritis
-can have severe reactions (hypotension, urticaria, angiodema, hypoxia, rigors, dyspnea, chills, fever, nausea, rash, renal tox)
-premed with tylenol and benadryl
-slow infusion to resolve some side effects, side effects reduce with each infusion
immune system
1st line: skin , ucous membrane, gut flora
second line: phagocytes:
3rd line antibodies, t and b cells
malignant tumor (cancer)
cell strcuture different from parent tissue, cell division uncontrolled, loosely adherent, invade neighboring tissue, establish blood vessels
Approaches to treatment
cure: prolonged absence of disease
control: no further growth
and palliation : comfort
neoadjuvant
therapy in the first step to shrink a tumor before the main treatment) surgery is given
-chemo, radiation, hormone therapy
adjuvant
therapy given afer primary treatment to lower risk of cancer coming back
-chemo, radiation, hormone, targeted and biologic therapy
myeloblation
obliteration of bone marrow with chemo in prep for blood stem cell or bone marrow trasnplant to destroy blood forming cells in the marrow and reduce tumor burden – destroy immune system so it cannot attack donated cells after transplant
nonmyeloblative
not as intense, chemo doses are not as intense
LESSON 2: Alkylating Agents
-cytoxan
-ifosframide
-bendamustine
platinum based chemo
consideration on age, kidney function, and concurrent use of radiation. both can cause nausea, vomiting, hearting loss, kidney function damage, electrlyte disturb. CBC chem panel and mag checked
-cisplatin: admin over longer period of time. nausea can last over a week
-carboplatin- risk with age >65, harder on kidney function. over shorter period of time, nausea within first 24 hours. neuro tox
cyclophasmide
hair loss 10-14 days post treatment
-can be given peripherally
-hemmorhagic cystitis – hydration is key, high dose may need bladder protection
-easier to give than iphosphamide
iphosphamide
neuro changes can occur- personality changes can occur, neuro checks before
central line only
-need a bladder protective agent 100% of the time
nitrosureas
cross blood brain barrier – can treat brain tumors. alkylating agents
-pulmonary monitoring
Lesson 3: Antimetabolites
-azacitidine
-capacitabine
-fluorouracil
-cytarabine
-decitabine
-methotrexate
inhibit DNA and RNA synthesis – can cause myelosuppression, GI toxicities, phospotsensitiivty, hand foot syndrome, vigorous I V hydration to prevent tumor lysis
5 fluorouracil (5 FU)
-IV oral topic and opthalmic formalation
-can cause hyperpigmentation, increased mucositis, photosensitivity, diarrhea
-capcytobine is the oral form – needs to be taken 2x day, hand foot syndrome can occur
-INR monitoring
methotrexate
antimetabolite, cell cycle specific to S phase
-cleared in kidneys – effects: hepatotox, renal tox, mucositis, nausea, myelosuppression, pneumonitis, photosensitivity, neurotoxicity, infertility
-yellow in color. renal function, hydrate 2-3L/ day, no alcohol use, sun exposrue, folic acid, avoid effusions
azacitidine
for treatment of myelodysplastic syndrome: group of cancers in which immature blood cells do not mature (SOB and fatigue are markers)
Lesson 4 A cautionary tale about routes
intrathecal chemo- injects chemo directly into the subarachnoid space so it reaches the CNA
-leukemia and lymphoma spreading to CNS since most chemo does not cross blood brain barrier
intrathecal chemo
ONLY methotrexate and cytarabine can be given IT
-IT hydrocorisone given at same time to reduce inflammation
vincristine
dilute in 20mL minibag and infuse over short time- IVP not reommended
vinblastine -dilute in 25-50 ns
Lesson 5 Antitumor Antibiotics
-anthracyclines: interfere with enzymes for DNA to replicate, work phases of the cell cycle
lifetime dose limites because they are cardiotoxic
-daunorubicin, doxorubicin, epirubicin, idarubicin
nonanthracycline: actinomycin, mitomycin, bleomycin
doxorubicin
vesicant
extravasation possible- must eval cardiac funciton, ongoing cardiac monitoring, hypersensitivity risk
-nausea/ vomiting, mucositis, diarrhea, myelosupression, hepatic impairment, secondary cancer
-cardiac: SOB< skipped beats, weight gain -myelosuppress: oral temp daily, report >100.5
GI: nausea vomiting diarrhea, inspect mucosa
neuro: numbness/ tingling, burning
GU: change in color of urine
dexrazoxane
cardiac protectant given before
bleomycin
antitumor antibiotic – lifetime dose warning
-can cause hypersensitivity, skin reaction
-report SOB< skin issues, protect from sun
Lesson 6 symptoms that can be dose limiting
chemo induced nausea and vomiting
-lead to dehydration, dec functional status, increased costs and withdrawal from treatment
-70% patient will experience.
RISK Factors: younger, history of low alcohol consumption, female, morning/ motion sickness
HEC: highly emetogenic – carmustine, cisplatin, cyclophosphamide, daarbazine, mechlorethamine, streptozocin
CINV
chemo infuced nausea vomiting- vomiting center is central area responsible for CINV
-patient are at risk for 2-3 days after last dose of cheom
Antiemetics
serotonin antagonists
-dolasetron, granisetron, ondansetron, palonosetron
neurokinin antagonists- aprepitant, fosaprepitant
steroids: dexamethasone
Cutaneous Side effects of chemo
5FU and capecitabine has been noted to cause the worst skin resactions
-hand foot syndrome
-palmar plantar erythrodysesthesia – painful- flaking swelling blisters and sores
avoid hot water, impacton feet and rubbing
myelosuppression
suppression of bone marroe, red blood and platelets
NADIR: point at which blood cell counts are at the lowest after treatemtn. usually 7-1 days after cyce
neutrophils heavily affected
platelets follow
erythrocyte loss appears later
NEUTROPENIA: risk of infection. fever >100.2 sign of infect
ANC reliable method to dtermine risk – 4,500-10,000 is normal WBC. ANC <1000 risk of infeciton
THROMBOCYTOPENIA: injury or loss of stem cell – suppression of platelets. petechiae, bruise, headache, hypotension, prolonged bleeding
ANEMIA: presents later dyspnea, fatigue, dizziness, headache -treatment: iron supp, bleed correction, transfusion, oxygen
Neutropenia
know when to expect the nadir
7-10 days after treatment. up to 6 weeks with some treatment
-ANC: reliable method to determine infcetion risk
polys + bands x WBC /100
fever >100.4 sign of infection
GI Toxicities
diarrhea, constipation induced by chemo is common – can cause fecal impaction
mucositis- can occur from the mouth to the anus
stomatitis- inflam of mouth
xerostomia- dryness of the mouth
Acute Infusion Reactions
hypersensitivity- uniphasic- immediate
biphasic- 1-72 hours later
anapylaxis- acute, severe inflammatory response that is sudden and systemic – dyspnea, hypotension and loss of conscious
GIVE benadryl or hydrocortisone, close vitals, STOP, maintain airway, resuscitation meds
Type 1 reactions
pruritus, restless, agitation, impending doom, fever, flushing, chills, urticaria, edema, rash, nausea, dyspnea, wheeze, hypotension, beonchospasm
Type IV reaction
cell mediated, delated. pneumonitis, mucositis, granuloma, GVH
Lesson 7 safety issues: cumulative dose
cumulative dosing can result in neurotox and nephrotox, alkylating, myelotox, hepatotox, cardio tox, pulmonary and GI tox
Lesson 8: safety issues: extravasation and vesicant admin
leak of antineoplastic meds from the vessel in which it is being administered into the surrounding tissue – non DNA binding remain in local area, DNA binding lead to tissue destruction
-cytotoxic drugs are classified as irritants and vesicant – irritants cause inflammation, burning or pain . vesicants can cause local blisters and xtensive damage to the tissues
NO PIVs in hand, wrist or AC – dont place below a recent venipuncture site
CHECK for blood return: 3ML of blood in 3 seconds. larger syringe diameter exerts less pressure on walls of catheter
NO BLOOD RETURN NO USE
IV access selection
determine dration of treatment- for peripheral access, small gauge plastic cannula is more suitable. alternative IV site from one arm to the other to preserve the veins
-CVADs
- cool compress for 24-48 hours then warm compress, hydrocorisone cream, elevate, pat dont rub, pain meds. check area for skin color canges, pain
PORT: should get a blood return
venous irritation
low pH, blood return may be present
lesson 9: plant alkaloids
-etoposide, docetaxel, paclitaxel, vinblastine, vinorelbine
vinca alkaloids given IV and should never be given intrathecal
Paclitaxel: shoud be stored in glass – through in line filter
Cabazitaxel: use in line filter
Nap paclitaxel: premeds not required
extravasation of plant alkaloids
topotecan and etoposside- irritants
-vinorelbine and irinotecan: irritants with vesicant properites: discoloration of sin, rash, phlebitis, urticaria, blistering, skin sloughing
lesson 10: biotherapy
treatment that uses substances made from living organisms to treat disease – stim or suppress the immune system to help fight cancer, infection and diseases. some attack specific cancer cells which keep them from growing
targeted therapy: uses drugs or other substances to identify and attack cancer cells
GOALS: disease cure, improve response or increase disease survival, control or stabilize disease, mtainain or enhance live
CATEGORIES: cytokines, monoclonal antibodies (conjugated and unconjugated), small molecule inhibitors, antibody durg conjugates, vaccines
Biotherapy terms
receptor: molecule in surgace that binds to a specific substance causing effect in that ell
-monomer- molecule that can join with others to form a larger structure called a polymer
-ligand: forms a complex with another to exert a biological effect
-ligand binding: attaches to receptor site and activates that receptor
-dimerization: signals
-kinase: adds chemicals to other molecules, causing other molecules to becomes active or inactive
-phosphorylation: activation of a chemical process to initiate signaling
-signaling pathways: group of molecules that work together to control a cell function
Targeted Therapies
extracellular: target receptors on the outside of the cell
-intracellular: target and interfere with processes inside the cell
attack many different targets – block angiogensis, block signals in or outside of the body, deliver toxic substances to the cell, stimulate the body’s immune system
Include: hormone therapies, signal transduction inhibitors, apoptosis inducers, angiogenesis inhibitors, immunotherapies
HORMONE THERAPY: adds, blocks, or removes hormones from the body to help slow the growth of cancer cellls
SIGNAL TRANSDUCTION INHIBITOR: block signal transduction
MONOCLONAL ANTIDOES: end in mab- rituximab, panitumab
SMALL MOLECULES
located in the cell because these agents enter more easily
-get into the cell, interfere with the internal components and disrupt the function, causing cell death
tyroisine kinase inhibitors: end in tinib: oral agents. be aware of adherence and interactions
-erlotinib, sunitinib, ponatinib, imatinib, dasatinib, ibrutinib
kinase inhibitors: oral agents
hedgehog pathway inhibitors: controls cell division of adult stem cells and cell differentiation. oral agents. be aware of adherence and interactions
IMMUNOTHERAPIES
trigger immune system to destroy cancer cells- make cell visible for immune system to destroy
-others help boost the immune systems ability to fight cancer.
include: monoclonal, immune checkpoint inhibitors, cancer vaccines, non specific immunotherapies, adoptive cell therapy, oncolytic virus therapy
monoclonal antibodies
man made versions of immune system proteins, used to treat cancer because they are designed to attack a part of a cancer cell
nonspecific immunotherapies
use proteins taht normally help regulare immune system to enhance the bodies immune response
-cytokines: interleukins
-interferons
adoptive cell therapy
help immune system fight diseases such as cancer and infections
lesson 11: safety issues, safe handling is about YOU too
carcinogens- a lot of cancer treatment drugs
risks of occupational exposure
routes of absorption- dermal, mucous membranes, inadvertent ingestions, inhalation, injection
-air samples, floors, drug vials, prep areas, skin under gloves
hierarchy of controls
anticipating, recognizing, evaluating and controlling workplace conditions that may cause injury or illness
-industrial hygiene uses the principle of hierarchy of controls when determining how to control a workplace hazard
drug administration
always remove first set of gloves before touching pump
-connect secondary tubing to allow for flushing of tubing
-place pad under work area, gauze around syringe connections for IVP, pad nder work area when attaching needles for SQ
oral: gloves, directly into a med cup
double ID name, DOB, date of admin, name, route, total dose and total volume, date and time prepared/ expired
apply gloves, gown, and then re glove over cuffs
postadministration precautions
-excreted in urine, breast milk, stool vomit, sweat, semen and vaginal secretions, saliva, other bodily fluids for 48 hrs (some drugs up to 5 days)
HANDLING body fluids of patients who have recieved chemo: gown and double glove, face shield if splash
at home: wear gown with back closure, double glove, double wash apart from laundry, detergent
management of spills
chemo spill kit- sign warning others, use PPE, chemo gown, respirator/ goggles, double glove- use absorbant pads and out in spill bag, use neutralizing solution and wipe, then wipe with water, remove PPE
-place bag in chemo waste contrainer
lesson 12: changing gears, administration of chemo and biotherapy
nurses responsibility: is vascular access device intended for appropriate use? will they adhere? is the plan appropriate? additional referrals? is drug vesicant? is tracking in place for lifetime dose limit?
assess patients readiess to learn, health literacy, preferred method of learning, barriers to learning
is this the right treatment plan? goal of treatment? venous access? side effects to addres before?
Administration considerations
routes: oral- convenient, decreased time in hospital, expensive, and difficulty with adherence, inconsistent adborption- food drug interactions
nursing: verify dose, PPE, no crushing (pharmacist must do so if NG)
SQ: ease, well tolerated, inconsistent absorption, increased fat could increase risk of misplacement. pain/ bleed/ bruising
IM: rapid absorption, can cause nerve damage, tissue necrosis, PPE, insert at 90 deg angle, avoid massage
intraperitoneal: catheter or IP port. directly into peritoneal cav, infection risk, abdominal pressure, bleeding, diarrhea, per, infection, anaphylaxis
intrathecal: CNS malignancies,methotrexate and cytarabine – surgical procedure, lumbar puncture is invasive
intrapleural
intravesicular: bladder cancer
intra aterial
IV – continuous or push (through fre flowing IV, attach at injection port, aspirate for blood, slowly admin at a rate of 1-2ml/min
-vesicant chemo admin: remain with patient through entire infusion if giving through PIV, limit to IV push or short infusion less than 30-60, no PIV for continuous. verify blood return every 2-5 mL for IVP, 5-10 min during short infusion
central venous catheters – blood return before during and after
symptoms of extravasation
swelling, loss of blood return, report of pain or burning. discontinue at first sign
Pretreatment care
patient education – explain diagnosis and treatment, empower participation, identify sympt to report, promote coping skills
VERIFICATION: checking that prescribed doses are WNL, appropriate time intervals between treatments, route, volume and rate are clearly stated, review labs, ensure questions addressed
*verbal and phone chemo not allowed
-printed drug reference, current evidence based guideleine, step by step checklist
for HIGH DOSE: risk of cardiac toxicit, neuro checks with high dose cytarabine (risk of cerebellar toxicity) high methotrexate given with leucovorin, myeloblation
Pre Administration
- online national comprehensive cancer network guidelines is most accurate source of info for evidence based practice guidelines
-need 2 nurses to verify dose calc
-ONS chemo safety standards requries reference to method of dose calc
Recommendations to Prevent Errors
-lack of method followed consistently, lab values, wrong prep methods, wrong sequence/ dose or route, schedule or timing, omissions, wrong rate or IV pump misprogram, wrong patient
Vascular access devices
PIV, midline, PICC, nontunneled central catheter, tunneled central catheter, implanted port, temp apheresis or hemodialysis, tunneled apheresis
IV considerations
no IV pump with PIV< stay with patient, less than 30-60 min infusions, blood return every 205 mL for IVP, 5-10 for short infusions
dosing- metric system: mg, mg/kg, AUC and mg/m2
weight based: based on body weight – weight on day of delivery is crucial
BSA dosing: m2
AUC: area under the curbe- carboplatin, drug concentration in the blood over a period of time, renal function part of calc
special considerations: older adults and young kids, poor nutrition, obese, prior radiation or chemo, comorbid conditions, myelosuppression
lesson 13: introducting bisimilars
Biosimilars: group of medicine products developed to mimic other drugs used for different indications
-biological product: vaccines, monoclonal antibodies, gene therapies, cellular therapies, blood and blood product
-they have no meaningful difference that alter efficacy or safety from reference prod
biologic product is biosimilar to reference prod and can be expected to produce the same clinical results
benefit: cost- far less expensive to produce than trade drug and reduce cancer care cost
most expensive antineoplastics: bevacizumab, rituxin, trastuzumab
neupogen first biosimilar
nursing indication for biosimilar
know if it is being used – confer with pharmacist to determine if available
-build safety profile
-know interchangeable policy
side effects not always the same
lesson 14: legal and ethical issues related to cancer
nurse is the last safeguard between appropriate accurate and safe dosing.
legal issues: med erros, unintended cytotoxic drug exposure, poor handling, spill, inadvertent exposure to the patient
document: calls to different agencies to find assistance for home therapy, meeting with home health nurse for prep, call to patient to notify that WBC low, location of PIV< conco with onc about DNR status, discussion with wife about birthday party
pretreatment assessment
patient history, diagnosis, MH/PSH, allergies, med review, symptoms, distress (need for social workers, counselors, religion), pain, fatigue
-height, weight, labs, diagnostic test (cardiac EF, etc), cancer during pregnancy, practices that promote safety, treatment plan, confirm order: 2 patient ID< date of admin, diagnosis, regimen, duration of treatmnet, cycle, criteria, allergies, dose calc, drug dose, route/ rate, length of infusion, supportive care
Patient PREP: inform, verbally review plan, provide a detailed explanation to the patient, family and caregiver, confirm name and ID< baseline vitals
PREP: PPE, infusion pump, ensure product match full name, ID, date of admin, generic name, route of admin, total dose,volume, date and time
CHEMO ADMIN: confirm plan with patient
PPE double check 2 patient IDs, drug name, dose, volume, rate, route, cycle, two signatures, rate setting, consent
-proper route, monitor patient immediate comp, document drug, patient ed and follow up
ETHICS
end of life, right to refuse or refuse consent, whether its truly infromed, conflicts, treatment of plan, patient advocacy challenge, confidentiality, scientific integrity, standards of practice, boundaries, issues related to investigational research
lesson 15: putting it all together
-patient education and care coordination
-treatment planning
-preparation and administration
Patient Education and care coordination
-enables active participation, provides explanation of disease and treatment, enables verbalization of understanding of treatment goals, improves quality of life, decrease costs, increase satisfaction
-education: name, rationale, side effects, meds to treat side effects, how to contact physician, testing – DOCUMENT
RCHOP (rituxin, cyclophsos, doxorubicin, vincristine, prednisone ) -cause neutropenia- dec in WBC that help fight infection. hand hygeine and stay away fro sick
Rituxin
can cause serious reaction usually in first dose- monitor closely for issues: report SOB, feeling of throat closing, chest pain, itching, watching heart, blood pressure, confusion/ agitation
cyclophosphamide
can cause hemmorhagic cystitis- irritation and inflammation of bladder that can lead to bleeding. watching for blood in urine, drink extra fluids, pee a lot and pee before bed
Doxorubicin
chemo that can damage the heart with a lot of it- monitor cumulative dose- in a lifetime. limit to this amount. MUGA scan to eval heart. before recieving drug. vesicant- irritating and damage skin and tissues id leaks, watch IV and skin close
vincristine
cause constipation and neuropathy- notify.
prednisone
steroid to reduce inflammation and lower immune response. used as part of many different chemo regimens. side effects that can cause high blood sugar, increased agitation or irritability, insomnia
Common questions
multiple drugs because cancer cells grow by going through cell cycle and dividing into more cells- different drugs work in different stages – this helps decrease possibility of drug resistance when cancer becomes smart and is less effected by meds
mononucal antibodies: agents that come from humans or mouse or both- they search out proteins on the cels surface. NK cells destroy the tumor like mABS- mABS ma cause harm to cells that are marked whereas chemo attacks all cells
-this is why chemo has effects on normal cells like hair follicles, oral,GI mucosa, blood cells etc
-adjuvant therapy: given following treatment to target minimal residual disease
use barrier methods following 48 hours of cehmo
NADIR: time when neutrophil count is the lowerst- varies by drug but is usually 7-10 days folowing treatment
Treatment planning
-social history could be barrier – risk of distress if no support , cats in home risk with handling is neutropenic
-history of asthma could be concerning
-use NCCN guidelines, research studies, protocols and chemoregimen to evaluate drug, dose and schedule
Lesson 1: Foundations to Set the Stage
Focusing on Cellular Structure and Function
The Normal Cell Cycle
-The cell cycle refers to the ordered seres of processes of DNA replication and mitosis, or cell division
-Cell nucleus regulates these processes by gathering and processing complexes molecular information
Interphase and Mitotic Phase
Cell division produces two identical cells through these two major phases
During interphase:
Cell grows and DNA is replicated through the following three steps:
1: First growth phase (G1 or first gap)
2: Synthesis phase (S phase)
3:Mitotic Phse (M phase)
First Growth Phase (G1 or first gap)
-cells increase in size
-reproduce RNA
-“quality assurance” test that the cell will be ready to synthesis DNA
-Length of time is variable, can be from hours to days
Synthesis Phase (S phase)
-DNA replicates
-Results in the formation of identical pairs of DNA (chromatids)
-which are attached a t the centromere
-lasts 2-10 hours
Mitotic Phase (M phase)
-Replicated chromosomes are aligned, separated, and move into 2 new, identical daughter cells
-takes about 30-60 minutes
Major points of cell regulation are entry and exit from
-G1 checkpoint
-S Phase
-G2 checkpoint
-M phase
Restriction Point
-The transition from the resting phase into an actively dividing phase (G0-G1) is a point where cellular transformation can occur
-During this time, cells pass through a transition phase known as a restriction point
-Extracellular growth factors trigger reentry into G1, and GF are required to send the cells past the restriction point, or the point of no return
G0 Phase (resting phase)
-After mitosis, cells may enter back into the G1 phase or go into a resting phase, known as G0
-Most cells in the human body reside in G0
-Exceptions to this are those that are (Resting in G0 phase)
-Exceptions to this are those that are metabollically active, such as
-granulocytes
-and the epithelium of the GI tract
Cell Cycling Time
Amount of time from mitosis to mitosis
Cell cycle video and image
http://highered.mheducation.com/sites/0072495855/student_view0/chapter2/animation__how_the_cell_cycle_works.html
Check points in the Cell Cycle: Keeping it All Under Control
-The cell cycle is carefully controlled through a series of checkpoints
-Variation in duplication or distribution of chromosomes during cell division can alter the genetic information passed on to daughter cells, leading to cellular dysfunction and disease, such as cancer
-These checkpoints monitor for DNA integrity and control progression through mitosis
Progression through the cell cycle is controlled through two proteins:
- cyclines (D, E, A, B)
- Cyclin-dependent kinases (CDKs)
-Cyclin-CDK complex allows the cell to progress through each phase of the cell cycle
Locations of proteins Cyclins (D, E, A, B) and CDKs
-(G0-G1) : Cyclin D and CDK 4/6
-Early S: Cyclin E and CDK 1/2
-Late S: Cyclin A and CDK 1/2
-G2: CDK 1/2 and cyclin A
-Before M: CDK 1 and Cyclin B
Inhibitory proteins
-prevent progression of the cycle when DNA damage is detected
-An example of an inhibitory protein is p53 (AKA TP53)
DNA Damage Checkpoints
-If DNA damage is present, cells are programmed to stop dividing or undergo apoptosis (programmed cell death)
-The retinoblastoma protein (Rb), p53, and p21 are some of the most well-understood inhibitory proteins (IP)
Inhibitory proteins p53
-Levels of this IP regulate several important target genes
-Will increase when DNA damage is present
-Protects against inappropriate signal proliferation
-sometimes called the “suicide gene”
M Phase Checkpoints
When the cells prepare to divide, the chromosomes line up in the mitotic spindle.
If the chromosomes are not properly aligned, division is not allowed to continue
Immunity
Cells of the Immune System
Pluripotent Stem Cell
-The cells of the immune system are created in the bome marrow from what is know as a _
-A stem cell that can differentiate into any cell type except for extraembryotic tissue, does not yet have a function
Myeolid Precursor Cells
Mature into:
-RBCS
-Plts
-WBCs (Granulocytes)
Lymphoid Precursor Cells
Mature into:
-Specialized WBCs called lymphocytes (Agranulocytes)
Lines of Defense: The Immune System’s Response to Attack
Consists of 2 types of immunity:
1: Innate
2: Adaptive
Innate Immunity
-First line of defense against a pathogen
-Does not retain memory of the entity
-Involves the following:
(skin, mucous membranes, and normal flora of the skin and gut)
(Cellular components such as phagocytes, natural killer cells, granulocytes, and macrophages)
- Phagocytes
- Natural Killer Cells
- Granulocytes
- Macrophages
1.Cells that engulf and destroy invader - Cells that sense receptors on self and non-self to determine if they should kill or not
- Type of WBC that have granules (Neutrophils
Eosinophils – parasites
Basophils – release histamine to stimulate immune response) - Large phagocytic cells stimulated by infection
Adaptive Immunity
-Stimulated if innate immunity is insufficient
-leads to immune system memory
-Humoral immunity
-Cell-mediated immunity
-Regulatory T-cells
Humoral Immunity
-B-Cells
-Memory B-Cells
-Plasma act to produce immunoglobulins (Igs) or antibodies
B-Cell
-each one is programmed to make one specific antibody
-Can recognize antigens whether they are freely circulating in the blood or attached to surface of a microbe
-When dividing, can become plasma cells which will then begin secreting antibodies that are unique to that antigen
Plasma Cells
-some plasma cells will undergo apoptosis
-Some will go to the BM where they will continue to secrete antibodies sometimes for years
Cell-Mediated Immunity
Depends upon cytotoxic T cells and helper T cells and their cyokinds
-more effective against antigens within cells
Regulatory T-cells AKA suppressor T-Cells
regulate the immune response to prevent autoimmune reactions and limit inflammatory responses
T-Cell
-Can only recognize antigens when they are presented to them by “presenting cells”
-Recognize phagocytized fragments of an antigen that are put on the surface of antigen-presenting cells
Helper T-Cells (CD4+)
-help other T-Cells by secreting chemicals
-Help B Cells to respond
-rapidly divide, in an effort to stay ahead of the antigen dividsion
-some will turn into effector cells, which secrete different kinds of cytokines
-respond similarly to B-Cells
Cytotoxic T-Cells (CD8+)
-Directly kill cells for which they are activated to kill
-rapidly divide, become mature cells, and start killing antigens
Cytokines
-Secreted by lymphocytes
-Tasked with eliminating the antigen
-Multifunctional subsances having proinflammatory, anti-inflammatory, and regulatory functions in the immune system
Cytokines Include..
-Interferons (IFNs)
-Tumor necrosis factors
-Transforming GFs
-Interleukins (IL -1, -2, -3, -4, -6, -8, -10, and -15)
-These cytokines regulate antibody production and the functions of B and T cells as well as interact with antigen-presenting cells and NKCs
Benign Tumors
-encapsulated and grow in an orderly manner with smooth edges
-Do not invade neighboring tissue
-DO not metastasize to distant sites
-the cells well differentiated in that they look like the parent cell
Characteristics of Cancer Cells
-Malignant tumors are not encapsulated
-Cell structure is different from parent tissue (no as well differentiated)
-Cell division is uncontrolled
-Cells are loosely adherent without contact inhibition
-Cells are able to invade neighboring tissue
-Cells can migrate and metastasize to distant sites
-Can stimulate the development of new blood vessels to supply the tumor (angiogenesis)
Proto-oncogene
-regulate normal cell growth and division
-large family of genes that code for proteins and enzymes that turn on the cell cyle
Oncogene
when mistakes in copies of DNA can occur, if a mutation occurs next to a proto-oncogene, it can “turn on” and become a __
Examples of oncogoenes
- EGFR or Erb-B1 (codes for an epidermal GF receptor in the receptor-tyrosine kinase family ad is associated with head and neck and colorectal cancers)
-EGFR inhibitor therapies are known to cause cutaneous reactions
- Erb-B2 or HER2/neu (codes for an EGFR protein in the tyrosine kinase family and is associated with some breast cancers)
Tumor suppressor genes
-act like brakes in a car, slowing down or stopping cell growth and division
-in the presence of malignancies, they bind to DNA with intention of repairing or activating apoptosis
-for it to be turned on it must be expressed or “opened” in the DNA helix so that it can be transcribed or copied
p53
-“sucidie gene”
-activates apoptosis when the cell is damaged beyond repair or too old to function
-more than 50% of solid tumors, the gene is mutated and unable to perform its normal function
Growth Signals
-cancer cells are able to find their own growth signals making them self-sufficient
Signal transduction
-the communication or passage of a message telling the cell to do a biologic process, such as make a protein, divide, or make new blood vessels
Signal transduction steps
- Messages usually sent from outside the cell where the messenger (ligand) first binds to the cell receptor which extended through the cell membrane
- These receptors ae called receptor tyrosine kinases
- To send the message through the membrane, the receptor often has to join with another recetor to become active and t autophophorylate
- This is called dimerization and can be the following:
Dimerization
- Homodimerization: binding with the same type of receptor, such as an epidermal GF receptor (EGFR) 1 receptor with another EGFR
- Heterodimerization: binding with a different kind of receptor, such as EGFR1 binding with EGFR2
Protein tyrosine kinases phosphorylates
-turned on by giving up a phosphate molecule
-the message is now send via a “bucket bridage”, or passing the message from one molecule to other signaling molecules until the message gets first into the cell nucleus
-where it is transcribed
Pathways
many pathways and crossalks signaling btw and among the different pathways, and they all have the power to control cell behavior in one way or another
mitogen-activating protein kinase (Raf-1/MAPK) pathway
-shown to decrease the benefits of some cancer drugs
-decrease disease-free survival time in some pts
mammalian target of rapamycin (mTOR) survival pathway
-play a role in resistance to some chemotherapy agents in certain pts by keeping cells that have been exposed to chemotherapy from undergoing apoptosis
-role in angiogenesis
phosphoinositide 3-kinases (PI3K)
-transduction enzymes that activate Akt, leading to cell survival, increased cell proliferation, and growith
Neoadjuvant Treatment
-treatment given as a first step to shrink a tumor before the main treatment, usually surgery
-examples: chemo, radiation therapy, hormone therapy
Adjuvant therapy
-additonal cancer treatment given after the primary treatment to lower the risk that the cancer can recur
-Examples: chemo, radiation therapy, hormone therapy, targeted therapy, or biologic therapy
Dose density
-refers to the drug dose per unit of time
-reduction of time between treatments to achieve higher concentration than in a standard treatment plan
Dose intensity
-amount of drug delivered over time
-smaller doses of chemotherapy given more frequently
Relative dose intensity (RDI)
-calculated by comparing the dose that the pt received to the planned dose of the standard regimen
Oral Chemotherapy
-greater challenge to adherence because the responsibility falls on the pt and caregiver
Nonadherence
-pt takes too few or too many pills
Overadherence
-when a pt believes a dose was missed or that “more is better”, too much medication may be taken, leading to increased toxicity
Factor affecting adherence
-provider relationship
-side effects
-necessity
-routinization
-support
-lifestyle fit
-cost
-medication knowledge
-pill burden
-regiment complexity
Lesson 2: Alkylating Agents
Alkylating Agents
-function by causing a break in the DNA helix strand, causing interference with DNA replication, which results in cell death
Alkylating Agent Subgroups
-Nitrogen mustards (cyclophosphamide{Cytoxin}, ifosfamide{Ifex}, bendamustine{Treanda})
-Platinum-based (cisplatin{Planitol}, carboplatin{Paraplatin}): do not possess an alkyl group
-nitrosoureas
Nitrosoureas
-subgroup of alkylating agents
-able to cross the blood-brain barrier (effective in treating some brain tumors, melanomas, lymphomas)
-Carmustine (BiCNU)
-Lomustine (CeeNu)
-Streptozocin (Zanosar)
-pulmonary monitoring recommended
Carboplatin (Paraplatin)
-Alkylazing agent
-possibility for a hypersensitivity reaction which is rash, urticaria, erythema, pruritis, rarely bronchospasm and hypotensision
-notify RN if itching, scratchy throat, difficulty breathing, rash
-Blood count, particularly platelets, monitored because thrombocytopenia is a dose-limiting toxicity
-Oral dosage: 1-5mg/kg/day
Cisplatin (Planitol)
-Alkylating agent
-nephrotoxic (IV hydration 2-3 L per day)
-severe N/V
-ovarian and testicular
Cyclophosphamide (Cytoxin)
-Alkylating agent)
-hemorrhagic cystitis (dysuria, hematuria, hemorrhage)
-DC treatment if hemorrhagic cystitis
-adequate hydration
Oxaliplatin
-Alkylating agent
-irritant and vesicant, extra caution with the IV site
-peripheral neuropathy is a dose-limiting side effect (exacerbated by cold temperatures)
-avoid cold drinks and foods, wearing gloves and warm shoes
-avoid breathing cold air
Intrathecal Chemotherapy
-injects chemo directly into the subarachnoid space so it reaches the CNS
-Often used to treat leukemia and lymphoma that has spread to the CNS since most IV chemo does not cross the blood-brain barrier
-only MTX and cytarabine via this route
-IT hydrocortisone is often given at the same time to reduce inflammation
-MUST be preservative free to avoid CNS irritation
Chemotherapy-Induced N/V (CINV) Risk factors
-younger
-have a hx of low or no alcohol consumption
-are female
-hx of morning sickness
-prone to motion sickness
-have had chemo previously
Types of CINV
-Acute: occurring within 24 hours
-Delayed: from 24 hour – 5 days after
-Breakthrough: Occurring despite treatment
-Anticipatory: triggered by taste, odor, memories, visions, anxiety r/t chemo
-Refractory: occurring despite subsequent cycles when treatment failed in earlier cycles
Prevention/Treatment of hand foot syndrome
-limit exposure of hands and feet to hot water
-take cool showers
-avoid exposure to sources of heat, such as using saunas or sitting in the sun
-avoid activities that cause unnecessary force or friction on the hands or feet, such as running or aerobics
-avoid contact with harsh chemicals used in detergents and household cleaning products
-avoid activities that require you to press your hand against a hard surface
-elevate your hands and feet when sitting or lying down
-gently apply skin care creams to keep hands moist
-wear loose-fitting, well ventilated shoes
Nadir
-point at which blood cell counts are at their lowest following treatment
-typically, but not always, occurs 7-10 days after the cycle is administered
Neutropenia
-ANC of less than 500/mm3 or
-less than 1000/mm3 with the expectation that the count will drop below 500 in the next 48 hours
Neutopenia RF
-older than 65
-hx of neutropenia with previous chemo
-previous chemo or radiation
-hematologic malignancy, uncontrolled or advanced cancer, or lung cancer
Neutropenic Fever
-temp of 38.3 or greater one time
-temp of 38 lasting 1 hour
Absolute Neutrophil Count
- (%segs + %bands) x (WBC) / 100
Mucositis
-inflammation of the mucous membrane lining the digestive tract from mouth to anus
-affects 40-100% of pts
Stomatitis
-specifically inflammatory conditions of the mouth
Xerostomia
-dryness of the mouth caused by damage to or dysfunction of the salivary glands
Hypersensitivity Reaction (HSR)
-body mounts an immunologic response to a foreign substance or antigen, resulting in local tissue injury
IgE-mediated
-immediate (within 5 minute) HSR, present like classic allergic reactions
T-Cell–Mediated
-Delayed hypersensitivity reactions, can occur any time after the immediate hypersensitivity window, even days or weeks
Type 1 HSR early S/SX
-pruritus
-restlessness, agitation, anxiety, feeling of impending doom
-fever, flushing, chills
-urticaria (hives)
-maculopapular rash
-edema of hands, face, and feet
-N/V
-dyspnea, wheezing, bronchospasm
-hypotension, cyanosis
-circulatory and respiratory collapse
Type IV HSR
-pneumonitis
-mucositis
-contact dermatitis
-granulomas
-Graph vs host disease
Lesson 7: Cumulative Dose
Cumulative dose
total amount of one antineoplastic agent given to the pt, adding up each time that the pt has received it
Cumulative lifetime dose
-“cumulative dose should not exceed…”
-total amount of specific antineoplastic agents that can be safely given over the course of a pt’s lifetime
Extravasation
-leak of a drug capable of causing tissue damage from the vessel in which it is being administered into the surround tissue
Irritant
-causes inflammation, pain, and burning but rarely causes tissue necrosis
Vesicants
-causes blistering and significant pain and tissue damage and destruction, leading to tissue death
Vesicants in PIVs
-Do not use IV in hand, wrist, AC areas
-Do NOT place the IV below a recent ventipuncture site used (<24 hours)
-Use a flexible IV catheter
When a vesicant extravasation occurs or is suspected, take the following steps:
- Immediately STOP administering the vesicant and IV fluids
- Disconnect the IV tubing from the IV device. Do not remove the IV device or noncoring port needle
- Attempt to aspirate residual vesicant from the IV device or port needling use a small (1-3 mL) syringe
- Remove the peripheral IV device or port needle
- Initiate appropriate management measures
Managing Non-DNA Binding Vesicant Extravasation
-Vinca Alkaloids (vincristine, vinblastine)
-Do not bind to DNA in healthy cells when they extravasate into tissue. Indirect effect on healthy tissue
-Treat with heat, elevation, and hyaluronidase local injection (spreads the vesicant through the tissue for faster metabolism of the vesicant agent)
-Usually results in less tissue damage
-Improves over a short period of time (days to weeks(
Management of DNA-Binding Vesicant Extravasation
–Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin)
-Binds to DNA in healthy cells when they extravasate into tissue
-When not immediately treated with dexrazoxane, the vesicant remains in the tissue and invades adjacent healthy tissue
-Likely to result in more tissue damage
-Left untreated, extravasations become larger and deeper, worsening over time (weeks to months)
Lesson 11: Targeted Therapy
How targeted therapy and chemo differ
-targeted therapies act on specific molecular targets on or within the cells that are associated with cancer, whereas standard chemo act on all rapidly dividing cells
-chemo has more SEs
-targeted therapy ae chosen and designed to interact with their target on or within the cells, whereas chemo were IDed becaused they kill cells
-targeted therapies are often cytostatic (they block tumor cell proliferation) whereas chemo agents are cytotoxic (kill tumor cells)
Goals of targeted therapy
-disease cure when used as primary or adjuvant therapy
-improving overall response or increase disease-free survival when used in combination with conventional therapies
-controlling or stabilizing disease
-maintaining or enhancing quality of life
-decreasing the severity of toxicities from other therapies
Receptor
-molecule inside or on the surface of a cell that binds to a specific substance causes a specific effect in that cell
Monomer
molecule that can join with other identical monomers to form a structure called a polymer
Ligand
a substance that forms a complex with another biomolecule to exert a biologic effect
Ligand Binding
process by which the ligand attaches to a specific receptor site and activates that receptor, activating the signaling pathway
Dimerization
two monomers that are side-by-side on the surface of the cell are paired and activated by a ligand, which causes a series of signals
Kinase
type of enzyme that adds chemicals called phosphates to other molecules such as sugars or proteins causing other molecules in the cell to become either active or inactive
phosphorylation
activation of a chemical process to initiate signaling
targeted therapies work by doing the following
- blocking angiogenesis
- blocking signals inside or outside the cell
- delivering toxic substances to the cell
- stimulating the body’s immune system
BCR/ABL
-fusion protein tyrosine kinase formed with a gene translocation occurs between gene 9 and 22
-gene abnormality called the Philadelphia chromosome seen in CML and ALL
VEGF
this is the primary angiogenic factor produced by cells
mTOR
-target of rapamycin
-a protein that tells cells when to grow, divide, and survive
Two ways that angiogenesis inhibitors work
- some intergere with action of VEGF which stimulates n ew blood vessel formation
- others target their molecules that stimulate new blood vessel growth
Small Molecule Compound Targeted Therapies
-end in -ib
-targets located inside the cell because these gents are able to enter cells more easily
-intracellular
-most given orally
Monoclonal Antibody Targeted Therapy
- end in -mab
-relatively large in size and therefore usually cannot enter cells
-extracellular or transmembrane
-man made version of antibodies that are designed to attack a very specific target on cancer cells
-usually from mice
Lesson 12: Immunotherapy
Immunotherapy works by
-stopping or slowing the growth of cancer cells
-stopping cancer from spreading to other parts of the body
-helping the immune system recognize cancer cells and increase its effectiveness at eliminating cancer cells
Passive Immunotherapy
-initate an antitumor effect but do not result in any immunologic memory
-require repeated administration to be effective
-includes monoclonal antibodies and cytokines
Active Immunotherapy
-capitalize on the immune system’s ability to remember a foreign invade
-mount an immune response against the tumor and hopefully remember the cancer cells long after treatment has stopped
-includes cancer vaccines
Specific Immunotherapy
-capitalize on tumor markers to specifically target and kill cancer cells
-examples are mAbs and cancer vaccines
Nonspecific Immunotherapy
-do no target cancer cells alone but rather stimulate a large immune response
-given adjuvantly to other anticancer treatment drugs
-examples are cytokines, interleukins, and checkpoint inhibitors
Lesson 13: Safe Handling
Hierarchy of Hazard Controls aimed at reducing worker exposure
- Elinination of the Hazard
- Engineering Controls:
- Administrative Controls
- PPE:
- Elimination of the Hazard:
-highest level of protection from a hazardous exposure
-substitute a less toxic substance for the hazardous material
-not feasible with drug therapy
- Engineering Controls
-second highest level of protection
-use of machines or equipment that isolate or contain the hazard to reduce worker exposure
-Examples: biosafety cabinets and closed-system drug-transfer devices
- Administrative Controls
-third level of protection
-safe handling policies
-procedures
-work practices
-education and training of those responsible for HD handling
- PPE
-lowest form of protection
-consisting of garments that provide barriers to protect workers from HDs
-places the primary responsibility for protection on the worker
Donning PPE
- wash hands
- inspect gloves
- apply first pair of gloves
- put on gown with gloves inside cuff
- second pair of gloves over the cuff
- put on eye and face protection
Doffing PPE
- Remove outer gloves turning them inside out
- remove the gown
- remove the face shield
- properly dispose
5.remove inner gloves
- wash hands
True statements related to drug dose calculation and administration
-the AUC calculation incorporates renal function as part of the equation
-Pts who have had previous radiation therapy or chemo are considered special populations with regard to a potential need for dose modification
-The AUC calculation is used for carboplatin dosing
-Children may metabolize drugs differently than adults; dose modifications are possible
What is a monoclonal antibody, and how is it different from chemo?
-mAbs are agents that are derived from human or mouse antibodies or a combination of the two
-mAbs search out proteins on the cells surface
-mAbs recognize and bind to specific anatigens on the cells surface
-natural killer cells and/or cytotoxic proteins of the immune system recognize and destroy the marked tumor cells
-mAbs can also directly induce cell death as well
-One of the biggest differences is that mAbs cause harm only to those cells that are marked or binded
–
Should I avoid my grandchildren and other family members when I am getting treatment?
-it is perfectly safe for you to have contact with your loved ones while getting treatment
-Hugging, kissing, and spending time together while eating are all safe activities
-Safety with bodily fluids is necessary for the first 48 hours after receiving chemo
Can I be intimate with my partner during treatment?
-you should definiely check with your HCP first to be sure
-traces of chemo may be present in vaginal fluid for up to 48 hours after treatment
-use of a barrier is recommended for this reason for at least the first 48 hours