pmcol final pt 2

adrenocorticosteroids

steroids secreted by adrenal glands in cortex

three categories of adrenocorticosteroids + examples

glucosteroids: cortisol

mineralocorticoids: aldoesterone

adrenal androgens: DHEA, androstenodione (testosterone and estrogen)

what is the major source of estrogen post menopause

androsteonodione

layers of adrenal cortex

how are adrenocorticosteroids regulated

1. stress amplifies CRH release from hypothalamus

2. CRH stimulate anterior pituitary to release ACTH

3. ACTH act on adrenal cortex to stimulate cortisol

4. negative feed back of CRH and ACTH when done

zona glomerulosa

mineralocorticoid release

zona fasciculata

glucocorticoids and androgens release

zona reticularis

glucocorticoids and androgens release

where does cholesterol come from

LDL

how are aderenocorticosteroids made

cholesterol turns to prenenolone in mitochondira (rate limiting step) under influence of ACTH

prenenolone diffuse back to cytosol and remainder of processing steps occur in SER

17 alpha hydroxylase is _____ expressed in the Zona glomerulosa

not; that is why prenenolone gets directed to mineralocorticoid path

metabolic effects of glucocorticoids on carbs

stimulate gluconeogenesis in liver → inhibit glucose uptake in muscle and adipose → increases plasma glucose

metabolic effects of glucocorticoids on proteins

breakdown muscle proteins to amino acids (used as substrates for gluconeogenesis → increase plasma glucose

metabolic effects of glucocorticoids on lipids

breaks down fats (lipolysis) to free fatty acids + glycerol (substrates for gluconeogenesis) → inc. plasma glucose

genomic path of glucocorticoids

1. induce lipocortin-1 (inhibit phospholipase A2)

2. inhibit arachidonic path → prostaglandin and leukotrine decrease

3. transpress inflammatory transcription factors + inhibit cytokine production + COX 2

inhibitory transcription factors (2)

NFkB + AP-1

cytokines that are inhibited due to genomic anti-inflammatory path

IL-2. IL-6, TNF-alpja

non genomic anti-inflammatory effects

cell membrane fluidity, inhibit MAPK and PI3K/ Akt path

how are the metabolic and anti-inflammatory effects of glucocorticoids granted

cortisol that circulates blood is bound to CBG and only free from can enter cells

signals glucocorticoid receptor to transcribe proteins involved in gluconeogenesis, lipolysis and inflammation suppression

what are three synthetic glucocorticoids

1. hydrocortisone

2. prednisone/prednisolone

3. dexamethasone

mechanism similar to endogenous cortisol

what are the 3 side effects of synthetic glucocorticoids

1. hyperglycemia/ early onset of diabetes

2. osteoporosis

3. risk of infections

where does aldosterone affect Na+ reabsorption

kidney, colon, sweat glands

where does aldosterone affect K+ excretion

kidney, colon

where does aldosterone affect H+ excretion

kidney

how does mineralocorticoids work/ signal

1. aldoesterone binds albumin to some extent in blood only free form can enter cells

2. signals via mineralocorticoid receptor —> ENac + Na-K ATPase → Na reabsorption to blood/ K+ excretion

3. H+ ATPase increased expression

although cortisol has affinity for MR, why is it ineffective in kidneys

because kidney expresses 11 beta-hydroxysteroid dehydrogenase type 2 that converts cortisol to cortisone that has no MR affinity

what are the 2 synthetic mineralocorticoids

fludrocortisone and desoxycorticosterone

mechanism similar to endogenous aldoesterone

what are the side effects of synthetic minteralocoticoids

hypolakemia, hypertension, metabolic alkalosis

addison disease + treatment

too little adrenocortical insufficiency → use hydrocortisone + fludrocortisone

Cushing syndrome + treatment

adrenal cortex produce excessive levels of cortisol

surgical removal/ radiotion for tumor, ketoconazole + metyrapne

ketoconazole

broad effect on all hormones ; non selective

used for Cushing

metyrapone

blocks final step in cortisol synthesis; selective treatment for Cushing

primary aldosteronism + treatment

adrenal cortex produce excessive aldoesterone leads to hypertension

spironolactone + eplerenone

metastasis

abnormal cell growth with potential to spread to other parts of the body

cancer fundamentally

these cells are heritable

G1 Phase

checkpoint to ensure cell is ready for DNA synthesis

S Phase

DNA synthesis (many of cancer drugs show efficacy)

G2 phase

Checkpoint to ensure cell ready for mitosis

M phase

mitotic phase where cell divides (another important target for cacner drugs)

G0 phase

quiescent/ dormacy phase

what are the 2 groups that genes importnat for regulating cell cycle

1. tumor suppressor genes

2. protooncogenes

tumor suppressor genes

repress cell cycle or promote apoptosis + inhibit cell division following irreversible DNA damage

BRCA

DNA repair proteins (part of tumor suppressor genes)

p53

tumor suppressor protein that marks damage and slows s phase down (is mutated in 50% of cancer)

oncogenes

mutated forms of normal genes that cause normal cells to grow out of control → cancer cells

proto-oncognees

genes that normally control how often a cell divides and the degree to which it differntiates or specializes

what happens when proto-oncogene turns to an oncogene

it becomes permanently turned on/ activated when its not supposed to be

how does proto-oncogene become an oncogene

what are the major 4 classes of oncogenes

1. growth factors and their receptors

2. signal transducers (between cell receptors and nucleus)

3. transscription factors/ nuclear transducers

4. programmed cell death regulators

neoplasms

cells that exhibit combinations of mutations

Knudson’s multiple-hit hypothesis

environmental factors hit genes to become faulty

what happens at the time of 30 cell doublings + another 10 doublings

2 cm diameter tumor, can be diagnosed by unnoticed in many organs

20 cm in diameter → lethal

therefore neoplasm is silent for ¾ of its existence

cancer is often advacned by what

time of detection

fundamental issue of cancer regarding cell number

you cannot leave any cancer cells behind after treatment ends

drugs will not have 100% efficacy maybe 99.99% (could still have 10 million cells left over!) → why surgery is best

what are some basic treatments for cancer

1/3 are treated with local treatment (surgery + radiotherapy). some use anti-cancer drugs due to metastasis

fundamental issue of cancer therapy regarding cells

they are your own cells! → a little protection because your immune system wont touch them (immune to immune activity)

therapies have narrow theraputic window because they are meant to be cytotoxic

what are some other cells that cehmotheraputic drugs attack

liver, and GIT because they rapidly divide

fundamental issue with cancer therapy regarding drug resistance (2 types)

primary drug resistance: present when drug is given (elevated TP proteins)

acquired drug resistance: result from adaptation from tumor cells or mutation (antibodies cannot bind)

if you kill the non-resistant cells you will give room to resistant cells to crazy proliferate

alkylating agents

nitrogen mustards + Cisplatin

cisplatin

aklylating agent that causes severe nausea and vomiting → can be nephrotoxic

revolutionalized treatment of germ cell tumors

how do alkylating agents work

form higly reactive electrophilic intermediates and bind covalently to DNA (esp. N7 guanine)

bifuncitonal to cross link DNA strands

when are cancer cells most susceptible to alkylating agents

in late G1 and S phase due to abundance of DNA targets

anti-metabilite chemotheraputics

mimics natural metabolites → interfere with biosynthetic paths → inhibt nucleic acid synthesis

what are some anti-metabolite chemotheraputics 3

anti-folates

pyrimidine analogues

purine analogues

methotraxate

(MTX) analog for folic acid

converted to polyglutamates (pG-MTX)

together MTX and pG-MTX halt de novo nt biosynthesis

3 pyrimidine base analogues

1. cytosine arbinoside(nucleoside)

2. gemicitbine (nucleoside)

3. fluorouracil

fluorouracil

nucleobase analogue

1. converted to F(UTP) and encorporated in RNA → slow translation

2. converted to dTMP which inhibits DNA synthesis

what are purine nucleobase analogues used for mainly

acute lymphoblastic leukemia

Vinca alkaloids

natural chemotheraputic derived from periwinkle plant

inhibits tubulin polymerization → distrupts assemplt of microtublules involed in mitiotic spindle M phase

paclitaxel

(taxanes) natural chemo agent from Pacific yew tree

promotes high affinity microtubule assemnly → affects M phase

camptothecins

bind and stabilize the short lasting DNA -topisomerase I → cannot re-ligate = accumulate single stranded breaks

S-phase (where DNA replication is happening)

antibiotics for cancer

doxorubin

bind DNA through intercalation = block DNA synthesis and cell replication

what are the 4 mechanisms of action for doxorubin

main focus

1. inhibit topisomerase

2. generate free radicals → stress → apoptosis

1. high binding affinity for DNA

2. bind cellular membrane to alter fluidity and ion TP

tyrosine kinase inhibitors

used to treat a type of leukemia containing Philadelphia chromosome

inhibits tyrosine kinase domain of Bcr-Abl oncoprotein

Philidelphia chromosome

specific genetic abonormality where choromosome 22 (BCR gene) and chormosome 9 (ABL 1 gene) combine

BCR-ABL leads to unregulated expression of protein tyrosine kinase activity → unreg cell division

cetuximab

a monoclonal antibody against extracellular domain of EGFR (inhibitor)

EGFR in cancer

over-expressed in a number of solid cancers and promotes cell growth, invasion and metastasis + angiogenesis (new blood vessels)

this dimerizes upon binding

tamoxifen

hormonal anti-cancer agent that is a selective estrogen receptor antagonist

blocks estrogen binding in estrogen sensitive cancer cells in breast tissue

innate immune system

first line of defense against pathogens non-specific + always exists

• skin/ mucous

• enzymes (lysozyme, acid hydrolases)

• immune cells: neutrophils, macrophages, natural killer cells, complement system

adaptive immune system guys

antigen presenting cells (dendritic cells and macrophages)

T lymphocytes

B lymphocytes (antibodies)

adaptive immune system

responds to pathogens in an antigen specific manner and previous antigen via memory response

3 ways to modulate immune system to our advantage

1. suppress it when immune response is unintended/ exaggerated

2. stimulate it when immune response is dampened

3. manipulate it for targeted immune response

immunosuppresants

supress unwanted effects of:

1. solid organ/ bone marrow transplant rejection

2. autoimmune diseases

3. hypersensitivity/ allergy

immune rejection is ____ as GVHD

not the same (host immune attack donor) ; graft versus host disease (donor immune attack host)

immunomodulators/ stimulants

activate immune to eliminate tumors

cancer immunotherapy (only cancer cells)

calcineurin inhibitors

immunosuppresant → cyclosporin A + Tarcolimus

removes phosphate (autocrine ligand is IL2 and IL2 secretion)

cyclosporin A

calcinuerin inhibitor that binds cyclophillin

tarcolimus

calcineurin inhibitor that binds FKBP → inhibit calcineurin (phosphatase) → inhibit NFAT translocation to nucleus → inhibit IL-2 production

more potent than cyclosporin

proliferation signal inhibitors

immunosuppresant → sirolimus + everolimus

binds to FKBP → inhibit mTOR → inhibit T cell proliferation (prevent cells from going