Targeting Microtubules

Vinca alkaloids: vinblastine & vincristine (M phase)

 extracted from plant vinca rosea

form complex with tubulin

blocking formation of microtubule

cause Mitotic arrest

Taxane: taxol

from bark of pacific yew tree

stabilize microtubule, promote assembly and inhibit disassembly

disturb M phase

Abraxane

 paclitaxel in albumin-coated nanoparticles

FDA approved for metastatic breast cancer

deliver taxol to specific area

nanoparticle reduce toxicity

Anti-tumor Antibiotics

1, Doxorubicin (none phase specificity)

a, inhibits topoisomerase II

b, intercalates DNA, RNA synthesis

c, alters cell membrane fluidity and ion transport which cause cardiac toxicity

d, generate free radicals

Etoposide

Topoisomerase II inhibitor

natural product, block cell cycle at S-G2 phase

it prevents DNA repair

Bleomycin

damage DNA, cause strand break, form free radicals

inhibits DNA synthesis @ stage G2

Toxicity of anti-tumor antibiotics

bone marrow depression, hemorrhage, anemia

GI ulceration, diarrhea

Alopecia (partial loss of hair)

Gonad depression, sterility

impaired healing

Renal damage (dead cancer cell excretion)

Teratogenic

Resistance to anti-tumor antibiotics

MDR (multi-drug resistant)

P-glycoprotein pump drug out

altered drug target

efflux through pumps

decreased uptake

altered membrane lipids

Hormonal Approaches (more selective)

Tamoxifen: competitive partial agonist/antagonist at estrogen receptors

suppress insulin-like growth factor 1 (IGF-1)

Upregulate transforming growth factor B (TGF-B)

1, Aromatase inhibitor: block convertion from T→E

↓ E in post-menopausal breast cancer pt.

2, GnRH inhibitor: block FSH & LH secretion

result 0 E for women, 0 T production for men

3, 5-Reductase inhibitor (anti-androgen)

eg: finasteride block synthesis of Dihydro-T

Drug of choice for Breast Cancer

E-Receptor+: aromatase inhibitor post menoposal

anti-estrogens (tamoxifen)

E-receptor negative : Doxorubicin

Docetaxel (semi-synthetic taxol)

Cyclophosphamide

Trastuzumab

Monoclonal anti-body: trastuzumab

HER2= EGFR inhibitor

block HER2 receptor (human epidermal growth factor)

↓ cell proliferation

↓ cell growth

Male Prostate Cancer

watch & wait in late 70s or 80s

surgery or radiotherapy

Hormonal therapy: GnRH agonist, androgen antagonist

Combination chemo: Estramustin+Taxol or vinca

estramustin=estrogen+nitrogen mustard

Hodgkin Lymphoma-MOOP

Mechlorethamine

Vincristine (starts with O)

Procarbazine (another alkylating agent)

Prednisone (kill lymphocytes by interaction with glucocorticoid receptor)

Non-Hodgkin Lymphoma- CHOP

Cyclophosphamide (Nitrogen mustard)

Doxorubicin (H)

Vincristine (O)

Prednisone

Bevacizumab

target vascular endothelial growth factor (VEGF-A)

block angiogenesis, tumor growth ↓

Imatinib=Gleevec (CML)

Chronic myelogenous leukemia produce Bcr-abl gene (tumor specific tyrosine kinase)

Gleevec works by inhibiting Abl group of tyrosine kinase

All-trans retinoic acid

promote terminal differentiation of leukemic promyelocyte

Immunomodulation:

interferon alpha produced by lymphocyte, involved in innate immune response against viral infection 

It interact with R, trigger signal transduction and affect gene expression

Result: enhance immune activity

decrease tumor cell proliferation