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The cells that don't age are cancer cells.
--Dr Flick


First of all, there are three types of cells: labile, stable, and permanent.

LABILE
divide from stem cells
three main locations: bone marrow, basement membrane of skin, crypts of intestine
drugs that suppress division of these cells-->diarrhea, rashes, anemia
(predictable, eh?)

STABLE
these cells are in the G0 phase, resting
tissues: smooth muscle, parenchyma of liver, spleen, kidney
takes hormonal or other stimulus to make them divide
ex: estrogen-->endometrial proliferation

PERMANENT
these cells are terminally differentiated and do not divide
hyperplasia impossible, hypertrophy is how they cope with increased load
ex: striated muscle, cardiac muscle, neurons

GENERAL CELL CYCLE OVERVIEW
G1 phase: mastermind, DNA patched up before anything else happens, organelles duplicated
S phase: synthesis, DNA and other supplies doubled, go from 2N-->4N
G2: tubulin synthesis, making the microtubules that pull the DNA apart
M = mitosis-->2x 2N cells that may go-->G0 (resting or permanent), or G1-->S phase



What is the most variable phase in the cell cycle?
G1, can be short or long-->dormant cell said to be in G0 phase
cells in G0 generally survive chemo
G1 known as mastermind phase
stop here before mutations are propagated
DNA is double checked before duplication
essential to life: control of the transition from G1 to S phase
Why?
cancer is loss of this control

What is normal?
when cell is ready and DNA has been checked
cyclin dependent kinase phosphorylates RB protein-->cell goes into S phase
this transition is inhibited by two genes: p53 suppressor and RB suppressor

RB SUPPRESSOR GENE
makes RB protein
-->actively inhibits cell cycle progression as long as it is not phosphorylated
phosphorylation performed by cyclin D/CDK4,6, then cyclin E/CDK2
if RB protein gene is knocked out-->cell goes S phase without control
there are two forms of RB prot:
if you have the wrong kind you have a much higher cancer risk



P53 SUPPRESSOR GENE
on xsome 17
p53 inhibits cyclin dependent kinase-->RB protein not phosphorylated-->cell stays in G1 phase and fixes things
called the guardian of the cell or of the genome
many functions:
--activate DNA repair proteins when DNA has sustained damage.
--induce growth arrest by holding the cell cycle at the G1/S regulation point on DNA damage recognition
--initiate apoptosis if the DNA damage proves irreparable
--inhibit angiogenesis
if knocked out-->kinase is always active-->always phosphorylating RB prot-->S phase



What virus inactivates both?
HPV
two products
E6 inactivates p53
E7 inactivates RB suppressor



What does RB stand for?
retinoblastoma
but RB suppressor is knocked out in many cancers:
breast, osteosarc, adenocarc of bowel

CHEMO
agents that are effective only against actively replicated cells are:
cell cycle specific
other agents are cell cycle non-specific
non-specific mb useful vs tumors with low % of dividing cells

growth rate of solid tumors in vivo usu initially rapid
then slows as tumor size increases
slowing dt limited nutrients, O2, dt limited vascularization
core of large tumor is slow growing so cell cycle specific chemo won't work
must remove body of tumor first, then use chemo to get the rest

DOSING
most chemo agents have narrow TI
usu delivered IV, some are oral
if regular IV dosing is needed a Hickman line, Port-a-cath or PICC line mb inserted
isolated limb perfusion in melanoma
isolated infusion of chemo to liver or lung has been performed

NORMAL TISSUES THAT ACTIVELY PROLIFERATE
hair
bone marrow
GI lining
buccal mucosa

SE's OF CHEMO
vomiting
stomatitis
alopecia
myelosuppression-->predisposes to infx
cardiac, pulmonary and bladder toxicities mb irreversible

HELEN LARKIN'S CERVICAL CANCER
HELA cells are the line used worldwide for cancer research
all came from this one woman

CHEMO DRUG TYPES OVERVIEW
anti-metabolite drugs
antibiotic-like drugs
alkylating agents (decr replication via purine inhib)
microtubule inhibitors (work at M phase)
steroid hormones and their antagonists
other ie: vinca, other plants with cytotoxins

ANTIMETABOLITES
methotrexate (MTX) also used for RA, SLE
6-mercaptopurine
(these first two most used)
6-thioguanine
fludarabine
cladribine
5-fluorouracil (5-FU)
capecitabine
cytarabine
gemcitabine

METHOTREXATE
class: ANTI-METABOLITE CHEMO, DMARD, immunosuppressive
INDIC: CA of lung, breast, head and neck, leuk, Hodg and non-H lymphoma, cutaneous T-cell lymphoma (mycosis fungoides), osteosarcoma, psoriasis, RA, and in prevention of graft vs host dz
MOA: can't utilize folate (like trimethoprine sulfa)
competitively inhibits dihydrofolate reductase, mostly stops S phase
high dosages may inhibit protein synthesis dt decr cofactors for folate
thus also arresting cells in G1 phase
don't give folate!!
CHAR: PO, IV, IM, PR. absorbed from GI via active transport. Renal excretion. Majority is eliminated in first 12 hours after admin, need 3L fluid. Need kidney and liver testing before and after.
SE: N/V/D, stomatitis, alopecia, myelosuppression
SE: neurotoxic-->peripheral neuropathies, rare pulmonary tox (reversible), liver damage. Teratogen and abortifacient. Has been used with misoprostol to induce abortion.

ANTIBIOTIC-LIKE DRUGS
doxorubicin
dactinomycin
daunorubicin
bleomycin

DOXORUBICIN
class: ABX like cancer drug
indic: breast, lung, esoph, gast and ov ca. Hodge and non-H lymphoma, sarcoma, myeloma, AML
MOA: inhibits DNA protein syn
CHAR: IV, large bore needle is used or in kids a subclavian line
SE: fatigue, N/D, anorexia
alopecia or a chemo perm: wavy hair, different from before
nausea is such a common and severe problem that anti-nausea drugs are given
"to cool down the CTZ"
pain, phlebitis at injx site
red-colored urine 1-2 days after dose also quite common

ALKYLATING AGENTS
"real poisons" --DrM
cyclophosphamide
mechlorethamine
carmustine
lomustine
semustine
isophamide
temozolamide
dacarbazine

CYCLOPHOSPHAMIDE
class: alkylating agent "poisons DNA"
**on boards!!!
indic: hodgkin's and non, AML, breast, ov, lung CA, multiple myeloma, sarcoma, CLL, mycosis fungoides, neuroblastoma, retinoblastoma
MOA: inhibits DNA replication, transcription of RNA, and nucleic acid function
CHAR: PO AND IV
SE: N/V/D, abdominal pain, nephrotoxicity.

MICROTUBULE INHIBITORS
vincristine
vinblastine
paclitaxel (taxol)
docetael
pacific yew, vinca tree bark, alkaloids

PACLITAXEL/TAXOL
class: microtubule inhibitor chemo
indic: advance ov ca or metastatic breast ca
MOA: reversibly binds B-tubulin subunit, promotes polymeriazation and stabilization of the polymer rather than disassembly, "tangles"
char: IV, hands and feet mb place in chilling mittens to keep fingernails from falling off, nails may grow back wavy (with a chemo perm)
SE: N/V, anorexia, change in taste, thinned or brittle hair, pain in joints of arms or legs lasting 2-3 days, changes in color of nails, tingling in hands or toes. phlebitis at inx site. change in bowel habits lasting over 2 days. fever, chills, cough, sore throat, difficulty swallowing, dizziness, SOB, severe exhaustion, skin rash, facial flushing and chest pain

STEROID HORMONES AND THEIR ANTAGONISTS
prednisone** boards
tamoxifen
aminoglutethimide
anastrozole
letrozole
exemestane
megestrol acetate
leuprolide
goserelin

TAMOXIFEN
class: estrogen agonist chemo
indic: 1st line tx of est-receptor positive breast ca
MOA: binds est receptor, blocks RNA synthesis
char: PO
SE: extreme estrogen fluctuations-->acute extreme hot flashes, N/V, skin rash, post menopausal vaginal bleeding, vaginal discharge
Risk: may incr risk of endometrial ca

MONOCLONAL ANTIBOTIES
end in "umab", used for RA, SLE
trastuzumab
rituximab
bevacizumab
cetuximab

TRASTUZUMAB
class: monoclonal antibody chemo
indic: metastatic breast cancer (usu to brain) (just one indication!)
MOA: binds HER2 sites in breast ca tissue and inhibits prolif of cells that overexpress HER2 protein, decreasing the # of cells in S phase
CA: IV, or intrathecal as it does not cross BBB
SE: fever, chills, N/V, abd and back pain. CHF.
Caution: in pts with cardiac conditions. Cardiac toxicity is worsened if Trastuzumab is given in combination with Anthracycline.

OTHER CHEMO AGENTS
platinum compounds
cisplatin
carboplatin
oxaliplatin
irinotecan
topotecan
etoposide

CISPLATIN
class: first platinum compound chemo
indic: solid tumors, carcinoma of bladder, mets from testicular carc, small cell lung cancer (oat cell-->cachexia) and ov ca (some carcinomas) and sarcomas, lymphomas, germ cell tumors
MOA: poisons DNA, reacts with DNA in rapidly dividing cells, binding to and causing cross-linking of DNA-->apoptosis of cell
CHAR: IV
SE: N/V, rash, high frequency hearing loss, tinnitis,
possible bone marrow suppression, possible anaphylaxis
hypomagnesemia, hypocalcemia
dose-related nephrotoxicity involving DCT and collecting ducts

TUMOR LYSIS SYNDROME
TLS
suspect in pt with large tumor burden who develop acute renal failure
with uric over 15mg/dl or phosphate over 8mg/dl
a group of metabolic complications that may occur during tx of ca
esp w/ lymphomas, leukemias esp ALL and AML
poorly differentiated lymphomas ie Burkitt's
has occurred with melanoma but much less common
caused by breakdown products of dying cells
like Herxheimer Rxn
solid tumor may involute spontaneously
complications: hyperkalemia, hyperphosphatemia (>8mg/dl), hypocalcemia, hyperuriciemia (>15mg/dL), hyperuricosuria-->acute uric acid nephropathy and acute renal failure
PREVENTION: give lots of fluids, support renal fx, give allopurinol
pts about to receive chemo for ca with high cell turnover esp lymphoma or leuk
should receive prophylactic oral or IV allopurinol (xanthine oxidase inhibitor, inhibits uric production) and IV hydration to maintain high urine output (>2.5L/day)
TRIGGERS: med cocktail usu includes chemo but mb triggered by steroid tx alone and can occur in the absence of treatment: spontaneous tumor lysis syndrome

SOURCES:
don't know where I got the genetic and cell cycle info
pharm info from Dr Miller's pharm 2 class, 2010

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