Anti Neoplastics

• Loss of Contact inhibition
• Lack of adhesion
• Unable to differentiate fully

Probably because they do not have enough blood supply

As time progresses with a tumor, the number of cancer cells in the tumor increases exponentially. Many treatments kill 99.9% of all tumor cells. However then you must allow time to recover. Early tumors kills 99.9% and leaves a handful of cells. Treatment in late tumors kills 99.9% of all tumor cells and leaves 10^6 cells.

• Heterogeneity of tumor with different cell types
• Low growth fraction
• Spontaneous mutation
• Activity of P-glycoprotein
• Increase in activity of topoisomerase I and II

We can get different MOA and a greater effect of killing, but no increase in side effects.

• MOPP for Hodgkin's Lymphoma
• mechlorethamin
• vincristine (Oncovin)
• procarbazine
• prednisone

• For Hodgkin's Lymphoma
• doxorubicin (Adriamycin)
• bleomycin
• vinblastine
• dacarbazine

• For Lymphomas
• cyclophosphamide
• doxorubicin
• vincristine (Oncovin)
• prednisone

• Anything that uses rapidly cycling cells:
• BM: Leukopenia, Thrombocytopenia, Anemia
• GI TRACT: Stomatitis, intestinal ulceration, diarrhea, N/V
• HAIR FOLLICLES: Alopecia
• GONADS: Menstrual irregularities, impaired spermatogenesis
• WOUNDS: Impaired healing
• FETUS: Teratogenesis

• Ototoxicity
• Cardiotoxicity
• Radition Recall
• Pulmonary toxicity
• Renal toxicity
• Hyperuricemia
• Peripheral neuropathy

DNA, specifically guanine, but also adenosine and cytosine

• Cross linking
• mispairing
• depurination
• ring cleavage

• Increase P-glycoprotein
• Increase in competing nucleophiles, such as cysteine
• Increase in DNA repair enzymes

• 1st Alkylating Agent indicated in HL and NHL
• IV, NOT PO
• UNSTABLE: Mixed with H20 immediately prior to IV
• A Vesicant
• SE: N/V, acute myelosuppression, teratogenic, repro organ inhibition

• Alkylating Agent indicated in CLL
• More stable, longer half-life, and PO in comparison to mechlorethamine
• SE: N/V, myelosuppression, risk of AML

• Alkylating Agent indicated in myeloma, ovarian, and breast cancer
• More stable, longer half-life, and PO in comparison to mechlorethamine
• SE: mild N/V, myelosuppression, risk of AML

• Common alkylating agent PRO DRUG indicated in HL, NHL, ALL, AML, CLL, CML, multiple myeloma, breast, lung, ovary, and severe RA
• Longest 1/2 life of mustards (7hrs.) given IV or PO, but ifosfamide is only IV
• Side effects include: BM depression, N/V, alopecia, hemorrhagic cystitis caused by toxic metabolite acrolein (counter with MESNA), amenorrhea, immunosupressant

• MOA: alkylate and carbamoylate (destroys proteins)
• Both ARE GREAT FOR PASSING BBB
• Indicated in brain tumors (obviously), HL, NHL, colorectal cancer, multiple myeloma
• SE: N/V, pulmonary toxicity, BM suppression

• Non-classical Alkylating agent
• MOA: metabolite is non specific cell-cycle alkylating agent; A PRO DRUG!!!!
• Indicated in HL, melanoma, and sarcomas
• SE: N/V, myelosuppression, teratogenic, repro organ sensitive

• Non-classical alkylating agent
• MOA: metabolite acts as a non-specific cell cycle alkylating agent; A PRO DRUG!!! ALSO VERY LIPOPHILIC
• Indicated in Brain tumors, malignant gliomas
• SE: N/V, myelosuppression, teratogenic, repro-organ sensitive

• A non-classical alkylating agent
• MOA: alkylating agent that inhibits mitotic checkpoints and induces mitotic catastrophe
• Indicated in CLL and NHL
• SE: N/V, myelosuppression, hypersensitivity

• Cisplatin, carboplatin, oxaliplatin
• MOA: Pt-guanine DNA crosslinking; inhibits DNA/RNA polymerase
• Indications: Testicular cancer, head and neck cancer, ovarian cancer, small-lung cancer, colon cancer
• SE: N/V, renal toxicity, ototoxicity, peripheral neuropathy, BM suppression (oxaliplatin is the least of these) (cisplatin the worst expect BM suppression---it's ok with that)

• Folic Acid inhibitors
• Purine Analog
• Pyrimidein Analog

• Folic Acid Analog (similar structure to dihydrofolate, tetrahydrofolate, and N5,N10-methylene-tetrahydrofolate)
• MOA: inhibit dihydrofolate reductase, resulting in reduction of one carbon transfers (needed for de novo synthesis of DNA)
• Indicated in oropharyngeal tumors, choriocarcinoma, acute childhood leukemia, acute psoriasis, rheumatoid arthritis, corticosteroid-dependent asthma, and immunosupressive agent/abortifiacient
• SE: BM, GI, renal toxicity (fixed by hydration and alkalinization), neurotoxicity, liver, Radiation Recall

Leucovorin is often administered with this drug

• Antifolate analog what is indicated for mesothelioma, non-small cell lung cancer
• MOA: targets mainly thymidylate synthetase, DHFR and enzymes involved in purine synthesis (GARFT and AICARFT)
• SE: myelosuppression, rash, mucositis, diarrhea
• Requires Folic Acid and V B12 to reduce toxicities

• A pyrimidine analog which is converted to fdUMP which inhibits thymidylate synthetase
• Indicated in solid tumros, breast cancer,carcinomas of GI tract
• skin keratosis/psoriasis
• SE: GI disturbances, myelosuppression, cerebellar ataxia, alopecia
• Leucovorin enhances the activity of 5-FU by stabalizing thymidylate synthetase a moer stable complex

• PO Prodrug of 5-FU indicated in metastatic breast cancer
• SE: N/V, diarrhea, less myelosuppression than 5-FU, no alopecia

• A cytosine molecule attached to an arabinose sugar (instead of deoxyribose sugar) that needs to be activated by addition of 3 phosphate groups
• Drugs are deactivated by deaminase activity/Activated by kinase activity
• Indicated for AML, ALL, CML
• SE: myelosuppression, GI disturbances, stomatits

• Similar to cytarabine
• MOA: inhibits DNA polymerase and ribonucleotide reductase
• IT can not be deactivated by deaminases, so longer 1/2 life
• Indicated in solid tumors, non-small cell cancer of the lung, pancreatic cancer
• SE: well tolerated, myelosuppression, N/V

Phosphoribosyl pryophosphate (PRPP) +Purine Base -----> purine ribonucleotide

With the help of HGPRT (hypoxanthine guanine phosphoribosyl transferase)

Hypoxanthine + PRPP-------------->inosinate------------->AMP/GMP

• hypoxamine analog which causes the formation of 6-TIMP (instead of inosinate)
• Indicated for ALL, CML
• SE: myelosuppression, GI

Metabolized by xanthine oxidase (allopurinol inhibits, thus increasing 6-MP effect)

• Prodrug for 6-Mercaptopurine
• Indicated for immunosuppression and/or RA
• Metabolized by TMPT (genetic problems can effect this)

• an analog of guanine
• MOA: competes for HGPRT (and PRPP) and damages DNA after incorporation/inhibits synthesis of AMP/GMP
• ISNOT metabolized by Xanthine Oxidase so not affected by Allopurinol like 6-mercaptopurine is

• Analog of adenosine
• MOA: converted to 2-fluoro-ara-ATP and inhibits DNA polymerase and ribonucleotide reductase
• Indicated in CLL
• SE: BM depression, N/V, neurological problems

• Analog of deoxyadenosine (with Cl-)
• MOA: activated by phosphorylation and incorporated into the DNA, it inhibits DNA synthesis and repair, and induces DNA strand breaks
• Resistant to deaminase
• Indicated in Hairy cell leukemia
• SE: myelosuppression, nephrotoxicity, neurotoxicity

• MOA: inhibits ribonucleotide reductase thus inhibiting DNA synthesis
• Indications: CML, solid tumors, sickle cell anemia, psoriasis
• SE: BM depression, stomatitis, GI ulceration, skin (hyperpigmentation and hyperkaratosis), radiation sensitizer, radiation recall

• NATURAL PRODUCTS
• MOA: disruption of MT in mitosis, thus inhibiting mitosis phase of the cell cycle
• Indications: HL, choriocarcinoma, testicular cancer, ALL, non-small-lung cancer
• SE: SEVERE vesicants, neurotoxicity (especially vincristine), alopecia, BM (especially vinblastine and vinorelbine)

• TAXANES
• MOA: build up of microtubules
• Indications: Breast, Ovary, Head and Neck, Lung
• SE: myelosuppression, peripheral neuropathy, hypersensitivity, fluid retention (Docetaxel)

• Epipodophyllotoxins
• Inhibit Topoisomerase II DNA repair enzymes
• Indicated in testicular cancer, small cell lung cancer episode
• SE: BM, GI, vesicants, secondary leukemia, radiation recall

• Camptothecins
• MOA: bind to Topoisomerase I complexes
• Indication: small lung cell cancer, metastatic cancer of ovary, colon, rectum
• SE: Diarrhea, myelosuppression

• Anthracenes:
• doxorubicin, doxorubicin-liposomal, daunorubicin, idarubicin, epirubicin
• MOA: intercalates DNA and binds Topoisomerase II
• SE: discolors urine RED, cardiotoxin reaction, myelosuppression, GI, radiation recall
• Indications: ALL, AML, Breast Cancer (epirubicin)

• a glycopeptide
• MOA: binds DNA and forms a complex with iron which breaks the DNA
• SE: pulmonary fibrosis, pulmonary toxicity, NO BM TOXICITY
• indicated for: Ovarian and Testicular cancer

• enzyme
• MOA: Destroys asparagine needed to make aspartic acid which limits protein synthesis....
• Indicated in ALL
• SE: hypersensitivity, CNS neurotoxicity, fever, liver and kidney failure, pancreatitis, excessive NH3, coagulation deficiencies
• IT DOESNOTCAUSE BM, GI, HAIR FOLLICLE PROBLEMS!!!!!!!!!

• MOA: induces differentiation of promyelocitic leukemia cells and induces apoptosis
• Indications: APL if tretinoin or anthracyclin did not work
• SE: rash, N/V, tachycardia, QT prolongation, (ventricular arrhythmia)

• MOA: induces APL cells to normal by binding nuclear receptor and affecting transcription
• Indicated in APL with no success with anthracyclin
• SE: Vitamin A toxicity, fever, skin dryness, rash, CNS toxicities, teratogenic

• toxic to lymphocytes
• works through glucocorticoid receptors to induce apoptosis
• SE: cushing's syndrome; also must withdraw slowly to prevent renal insufficiency

• monoclonal antibody that inhibits EGFR
• often combined with irinotecan
• SE: severe infusion reaction, instertial lung dz

• same as cetuximab but fully human AB instead of chimeric
• less SE

• UNDER GO CYP3A4 metabolism
• inhibitor of EGFR-TK
• only increase survival, donot cure :(
• SE: NO PREG, GI perforation, prior radiation

• MOA: competitive inhibitor of ATP binding site on c-abl, c-KIT, and PDGFR tyrosine kinase
• Indicated in CML
• SE: typical

• like imatinib, but higher affinity
• Indicated for all imatinib R CMLs except T315I mutation

• Like Nilotinib
• HIGHER MYELOSUPPRESSION

• MOA: inhibits phosphorylation of tyrosine kinases
• Indication: Advanced Renal Cell Carcinoma
• SE: Rash, GI, hand and foot syndrome, hypertension
• METABOLIZED BY CYP3A4