Block 4: Chemo-Natural Products

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5 Classes of Natural Products

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1. Vinca Alkaloids
2. Taxanes
3. Epipodophyllotoxins
4. Camptothecin derivatives
5. Antibiotics

(CA VET)

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These are two of the most powerful plant derived anti-tumor agents known.

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The vinca alkaloids:
Vincristine and vinblastine

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MOA of vinca alkaloids

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Binds Tublin in a 1:1 molar ratio, shifts equilibrium to favor depolarization --> disrupts microtubule formation

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Consequene of vinca alkaloids

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(-) spindle formation and mitosis

Cytoskeletal movement disrupted

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Do vinca alkaloids hang around in the plasma?

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Nope, they rapidly disappear

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Toxicity of Vincristine

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Neurotoxicity
Secretion of ADH

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Toxicity of Vinblastine

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Myelosuppression and mucositis

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Vinorelbine and toxicity

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Synthetic derivation of vinblastine, more specific for microtubules
Toxicity leads to granulocytopenia.

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Name two Taxanes

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Paclitaxel (Taxol)
Docetaxel (Taxotere)- synthetic analoge of Taxol

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Where does Taxol come from?

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The bark of the western yew tree Taxus brevifolia

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Principle use for Taxol (Paclitaxel)

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Breast and ovarian cancer
Also used for the prevention of restenosis in coronary artery stents

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MOA of Paclitaxel

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Promotes STABILIZATION and assembly of microtubules by inhibiting disassembly --> blocks reorganization of spindle fibers during mitosis

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PK and Admin of Taxol

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Continuous i.v.
Metabolized by liver

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Toxicities of Paclitaxel

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Neutropenia, mucositis, cardiac arrythmias in pts. who have recieved other cardiotoxic drugs

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Name two epipodophyllotoxins

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VP-16 (Etoposide)
VM-26 (Teniposide)

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Where do epipdophyllotoxins come from?

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Semisynthetic glycosidic derivatives of a podophyllotoxin derived from the mandrake plant.
(Now, I thought the mandrake plant was used to revive people who had been petrified?) :)

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When do you use epipdophyllotoxins?
(It's a useful son of a gun)

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Treatment of Hodgkins, diffuse histiocytic lymphoma, small cell carcinoma

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MOA of Epipodophyllotoxins?

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(-) Topoisomerase II

Epipodophy II otoxins

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Toxicities of epipodophyllotoxins

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Leukopenia
Thrombocytopenia

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Camptothecin derivatives: name two, derived from

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Irinotecan and topotecan
Plant alkaloid camptothecin

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Use of Irinoteca and its toxicities

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Lung and colon cancer
Neutropenia and diarrhea

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MOA of Camptothecin derivatives
(hit in the review)

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(-) of Topoisomerase I

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Dactinomycin (Actinomycin D)

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Antibiotic that intercalates between adjacent G:C Base pairs.
Low [] (-) RNA syn, High [] (-) DNA synthesis and RNA synthesis

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PK of Act D (t1/2 too!)

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Rapidly absorbed into tissues, mostly excreted unchanged
t1/2 = 36 hours

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Toxicities of Act. D

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Myelosuppression
GI
Erythema
RADIATION SENSITZATION

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Name 4 Anthracyclines (these are antibiotics too)

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Daunorubicin*
Doxorubicin*
Epirubicin
Mitoxantrone

*most widely used

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MOA of Anthracyclines

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DNA intercalation
Introduction of single stranded breaks

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PK of Daunorubicin and Doxorubicin

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Rapidly taken up into the heart, kidney, liver, lung, and spleen

Significant metabolism by the liver

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Toxicities of Anthracyclines

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Myelosuppression, mucositis, cardiotoxicity manifested by arrythmias and digitalis unresponsive CHF.

Cardiotoxicity reduces glutathione peroxidase (more susceptible to oxidative injury)

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What can we give to reduce cardiotoxicity from Anthrcyclines?

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Dexrazoxane- Fe chelator (-) free radical formation

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Antibiotics used for chemotherapy

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Dactinomycin
Anthracyclines
Bleomycin

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Bleomycin

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Antibiotic w/DNA binding region and Fe binding region

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MOA of Bleomycin (take a deep breath)

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Depurination and depyrimidation --> strand breaks

The detailed version: The S peptide binds to DNA, bridging the A2-Fe2+ complex into a postion in which oxidation is facilitated

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PK of Bleomycin

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Found in high [] in skin, lung, and tumor tissue
Eliminated by kidneys

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Toxicities of Bleomycin

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Subacute or chronic pneumonitis
Skin lesions