Anti-cancer drugs

nature (genetic) components of Cancer (etiology)

inherited cancer syndromes(p53, BRCA1), immune deficiency syndromes, polymorphisms

Nurture component of developing cancer (etiology)

• radiation

• chemotherapy

• Viruses/bacteria

• repeated injury(acid reflux, hepatitis)

• workplace exosures

other environmental factors that can cause cancer(4)

• food additives (nitrites)

• pollution (asbestos)

• occupational (benzene)

• industrial ( soot)

other lifestyle factors that can cause cancer

• tobacco

• alcohol

• diet

• viruses

promoter initiator model suggest

initiator must occur first followed by promoter (all at once) to cause cancer

tumor initiators (mutagens)

• x rays

• UV light

• DNA alkylating agent

tumor promoters (proliferation inducers)

inflammation (hepatitis)

alcohol

estrogen/androgens

EBV

malignant

cancerous tumor that invade surrounding tissues

benign

non cancerous: tumor has no effect on surrounding tissues

metastatic

individual cells break away and start a new tumor

G1 phase

cell grows and prepare to duplicate chromosome

S phase of cell cycle

synthesis phase where chromosomes are duplicated

G2 phase

second check stop, prepares to divide

M phase

mitosis phase- cell division occurs

G0 phase

cell cycle arrest- cell is in resting state

oncogene

Genes in our cells control various aspects of cell behaviour, including growth, division, and death.If an oncogene is mutated or activated, it can send signals to the cell to grow and divide uncontrollably by bypassing checkpoints

tumor suppressor gene

a protein that is involved in suppressing cell division. when mutated it is no longer functional

normal function of tumor suppressor genes

maintains genomic integrity (DNA repair, chromosome segregation)

what is often the 1st mutation in a developing cancer

mutations in tumor suppressor genes

examples of cytogenetic abnormalities (2)

• translocation

• aneuploidy

Philadelphia chromosomes

Oncogene rearrangement associated with variety of leukemias

imatinib

a tyrosine kinase inhibitor used to treat leukemias

polyp aka

benign

malignant epithelial cancer nomenclature

carcinoma

mesenchyme nomenclature

sarcoma

hematopoietic nomenclature

leukemia, lymphoma, myeloma

hyperplasia

increased number of cells

hypertrophy

increased size of cells

dysplasia

disorderly prolifertion

neoplasia

abnormal new growth

anaplasia

lack of differentiation

-Oma suffix means

benign (adenoma, lipoma)

benign vs malignant presentation

benign: well defined borders, well differentiated, regular nuclei

malignant: irregular borders, larger/irregular nuclei, more frequent mitoses

detection tools of cancer

blood work

palpation

symptomatic

CT scan

PET/SPECT scan

MRI

chemotherapy is most effective when….

growth fraction is high (% of cells not in G0)

purposes of chemotherapy (4)

• primary= shrink or eliminate tumor

• neoadjuvant= make tumor more susceptible for other therapies

• adjuvant= eradicate micro metastasis

• palliation= symptom control

“CR” response to chemo

complete disappearance for at least 1 month

“PR” response to chemo

50% reduction in tumor size or markers and no new disease for 1 month

“SD” response to chemo

no reduction or growth

“progression” response to chemo

25% increase in tumor size

fractional kill hypothesis

chemotherapies are given in cycles to allow normal cells to recover, while also allows remaining cancer cells to recover and develop resistance

how to reduce chance of tumor cells developing resistance to treatment

• use high doses (dose escalation)

• minimize recovery intervals of cycles

• employ scheduling during combo therapy

non cell cycle specific agent are also known as

genotoxic agents : alkylating and intercalating agents

which cell cycle specific agents target S phase

anti metabolites

which cell cycle specific agents target mitosis

cytoskeletal inhibitors

which cell cycle specific agents target G2 phase

topoisomerase inhibitors

which cell cycle specific agents G1 phase

steroid hormones

Cisplatin class

genotoxic agent (NCCS)

Carboplatin class

genotoxic agent (NCCS)

doxorubicin class

genotoxic agent (NCCS)

cyclophosphamide class

genotoxic agent (NCCS)

oxaliplatin class

genotoxic agent (NCCS)

multiple MOA of genotoxic agents (NCCS) (3)

• alkylation of DNA bases

• inter/intra strand DNA cross links

• induce mispairing of nucleotides

which genotoxic agent (NCCS) has the least adverse effects

cyclophospamide

ADR of common genotoxic agents (NCCS)

• GI effects

• hair loss

• renal toxicity (w/ cisplatin)

• ototoxicity(W/ cisplatin)

• CHF (w/ doxorubicin)

• bladder effects with (cyclophosphamide)

three types of antimetabolites

• folate antagonists

• purine antag

• pyrimidine antag

MOA of antimetabolites

prevents cells from carrying out vital functions able them to grow and survive

interfere with the production of nucleic acids, RNA, DNA(if new DNA cannot be made, cells are unable to divide)

methotrexate class

folate antag. ( antimetabolite)

Folate antag (methotrexate) MOA

inhibits dihydrofolate reductase, and enzyme involved in forming purines and pyrimidines nucleotides for DNA synthesis

methotrexate indications

leukemia, lymphoma, head and neck cancers, breast cancer, bladder cancer, RA

MOA of purine antagonists (5-FU, ARA-C)

inhibits Thymidylate synthase which is responsible for the synthesis of pyrimidine-containing nucleotides (C,T,U) which then stops DNA/RNA synthesis and cell division

5-fluorouracil (5-FU) class

pyrimidine antagonist (antimetabolite)

Cytarabine class

pyrimidine antagonist (antimetabolite)

5-FU indications (8)

Colorectal cancer

breast cancer

pancreatic cancer'

stomach cancer

genitourinary

liver

skin

esophageal cancer

purine antag indication (3)

• leukemia

• IBS

• organ transplants

importance of thiopurine methyltransferase

it metabolizes thoipurine drugs and when theres a defect it will prevent inactive metabolites and cause cell death

MOA of cytoskeletal inhibitors (vinca alkaloids, taxanes)

affects the mechanics of cell division (microtubules)

taxanes MOA

interfere with disassembly of the microtubules responsible for separating chromosomes

vinca alkaloids MOA

interferes with assembly of microtubules responsible for aligning chromosomes during metaphase

vincristine

vinca alkaloid

vimblastin

vinca alkaloid

Paclitaxel class

taxane

docetaxel class

taxane

vinca alkaloid and taxane indications

• breast cancer

• testicular cancer

• Hodgkin disease

• childhood leukemia

• muscle cancer

• neuroblastoma

Vinca alkaloids side effects

• GI problems

• loss of WBC and platelets

• High BP

• sweating

• depression

• muscle cramps

• heachaches

• peripheral neuropathy

• constipation

• hair loss

taxane side effects

• N/ V

• loss of appetite

• thinned hair

• joint pain

• nail colour change

• bruising

• fever/chills

• difficulty swallowing

• skin rash

• female infertility (ovarian damage)

MOA of topoisomerase inhibitors (G2 phase)

interferes with DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone that harm the integrity of the genome= apoptosis

topotecan class

G2 phase, topoisomerase 1 inhibitor

irinotecan class

G2, topoisomerase 1 inhibitor

etoposide class

G2 phase, topoisomerase II inhibitor

teniposide

G2 phase, topoisomerase II inhibitor

MOA of hormone therapy (g1 phase inhibitors)

starve cancer cells from hormonal signals necessary for growth

indications of hormone therapy (4)

• breast cancer

• ovarian cancer

• prostate cancer

• endometrial cancer

types of hormonal therapies (3)

• selective estrogen receptors modulators (SERMS)

• aromatase inhibitors(AI)

• selective androgen receptors modulators (SARMS)
  

tamoxifene class

SERM

raloxifene class

SERM

toremifene class

SERM

Selective estrogen receptor modulators(SERMs) AND aromatase inhibitors indication

breast cancer

high risk pop of invasive breast cancer

endoxifen

primary metabolite of tamoxifen via CYP 2D6( CYP 2D6 polymorphism results in lower endoxifen formation an drug effectiveness)

exemestane class

aromatase inhibitor

anastrozole class

aromatase inhibitor

letrozole class

aromatase inhibitor

flutamide, bicalutamide class

antiandrogens

combination therapy of different cancer drugs can result in (benefits) 3

• synergistic effects

• decreased development of resistance

• broader cell kill

Tamoxifen has drug interactions with

antidepressants

increased concentration of Dihydrofolate reductase is a mechanism of _________and is _________[drug name] resistant

resistance,

Methotrexate

cellular mechanism of drug resistance to chancer drugs 3

1. upregulation of target enzymes (DHFR)

2. failure of drug to enter cancer cells (increased efflux via P-glycoprotein)

3. enhanced survival

rituximab class

monoclonal antibody therapy

rituximab mechanism

binds to CD20 antigen present on the cell surface of B-cells and inhibits proliferation of lymphocytes and lymphoma cells

Trastuzumab

monoclonal antibody that binds to HER2