Anti- ca. Drugs: alkylating agents, anti metabolites, and antitumor abiotics

ANTI-BIOTICS against ca.Dactinomycin Doxorubicin and Daunorubicin Bleomycin

CCNS/CCS CCNS CCSMech of action Forms complex between G-C so

now DNA dep’ RNA polymerase can’t’ work

1. intercalation in the DNA blocking DNA RNA syn

2. membrane disruption3. O2 radical production by P-450

which damagese DNA

Interacts with topoisomerase II…Cells accumulate and get stuck in G2 phase and mitosis

Resistance 1. efflux pump= P-glycoprot2. DNA repair

efflx by P-glycoprot 1. efflux2. DNA repair

Clinical uses Combo with surgery for Wilm’s tumorCombo with MTX for gestational choriocarcinoma

HD (ABVD regimen)Breast lungALL, AMLKaposi sarcoma

TesticularSquamous cell carcinomaHL

Administration Iv Iv s.c., im, ivPharmacokinetics Bile and urine excretion Bile and urine excretion Kidneyssideefx BM depression, stomatitis,

alopeciaCardiotoxicity Pulmonary toxicity ( pneumonitis and

death), fever because doesn’t get inactivated in the lung as good as other parts of the body

Extra notes Reverse sideefx by dexrazoxane= zinecard, this chelates Fe

ALKYLATING AGENTS against ca. all CCNS

Mechlorethamine “nitrogen mustard”

Cyclophosphamide and ifosfamide “nitrogen mustards”

Nitrosoureas (NU)= Carmustine and lomustine

Busulfan

CCNS/CCS CCNS CCNS CCNS CCNSMech of action Reactive intermediate,

alkylates the guanine residue of DNA molecule

Breakdaown to active compound phosphoramide mustard and acrolein for cytoxicity upon the DNA

can x BBBalkylating metabolites which will cause cross linking of DNA inhibiting syn

Resistance 1. perm of drug2. conjugate thioles like

glutathion3. DNA repair

1. perm of drug2. conjugate thioles like

glutathione3. DNA repair

1. rxn w/ thiols

2. DNA repairClinical uses HL (part of MOPP) Burkitts

Breast, ovarian, NHL, CLL, CML, ANLL, ALL, Myeloma, neuro and retinoblastomas

Good for Brain tumorsAlso HD, NHLinulinomas

CML @ low doses

Administration Iv Unique: taken orally Carmustine – ivLomustine – oral

Pharmacokinetics Excreted in feces via bileAlso urine by GF

kidney

sideefx BM depression, can cause latency for v’sGI disturbances

Hemorrhagic cystitis due to acrolein

Hematopoeitic depressionCNS depressionRenal toxicityPulmonary fibrosis

Myelosuppression

Pulm fibrosisExtra notes Use iv MENSNAwhich

will inactivate the toxic compounds

Cytotic actins don’t appear to exted to either the lymphoid tissue or GI

ANTIMETABOLITES against ca.MTX 6- mercaptopurine

(6-MP)6- thioguanine (6-TG)

5- flurouracil Cytarabine Fludarabine (FAMP)

CCNS/CCS CCS (on S phase) CCS (on S phase) CCS (on S phase) CCS (on S phase) CCS S phase) CCS (on S phase)Mech of action

~ folate… inhibits dihydrofolate reductase… so in tetrafolate

Uses HGPRT to inhibit purine metabolism… dysfx RNA and DNA results

Analogue of pyrimidine… interferes with conversion of deoxyuridylic acid to thymidylic acid

Analogue of pyrimidine…Inhibits DNA polymerase (which is S phase)

Analogue of unnatural purine…

Resistance DHFRreduce influx of MTX

1. loose ablility to convert the drug to active form

2. thymidilate synthetase

3. rate of drug catbolism

Clinical uses AL, NHL, cutaneous lymphoma, Burkitts, breast ca. Head and neck ca.

ALL and CML AML Breast, ovarianColorectal, gastric

AMLALLCNS leukemia

Hairy cell leukemia

Admin’ Low- oralIntermediate- imHigh- iv

Iv iv

Pharm-kinetics

Metab in liver (first pass)

Urinary excretion

sideefx Myelosuppression, rashabortifacient

hepatotoxicity hepatotoxicity BM depressionUlcers in oral and GI mucosa

Severe myelosuppression, ataxia, dysarthria, dys-diadochokinesia , cerebellar disorders

myelosuppresion

Extra notes Leucovorin replenishes folate

Can combo with daunorubicin and cytarabine

*one of the most active drugs in leukemias

MICROTUBULE INHIBITORS against ca.Vincristine (ONCOVIN) Paclitaxel and Docetaxel Etoposide (VP16) , Teniposide (VM-26)

CCNS/CCS CCS Mech of action CCS that blocks mitosis in metaphase

Prevents chrom segregationTherefore inhibits microtuble formation

Freezes in polymerized state and stabilizes the microtub assembly

Binds to topoisomerase IIWorks on G2 phase

ResistanceClinical uses ALL in children, wilms, NHL

HLAdvanced endometrial caa.Metastatic breastSmall cell lungSquamous cell carcinomaHead and neck

Prostate Testicular ca.Small cell lung

Admin’ IvPharm-kinetics Metab in liver Metab in liversideefx Neurotoxin: phlebitis or cellulitis NeutropeniaExtra notes Part of MOPP for HL Premedicate with dexamethasone (a

corticosteroid)Podophyllin alkaloids

STEROID HORMONES against ca.Adrenocorticosteroids: prednisone, dexamethasone

Tamoxifen Estrogen Leuprolide and gosereline

Flutamide

What is it? Steroid, SERM: selective esterogen receptive modulator

nonapeptide Nonsteroidal antiandrogen

Mech of action Prednisone reduced by dehydrogenase, steroid binds to receptor which is for specific proteins

Block production of LH and syn of androgens in testes

LHRH agonists onto the LHRH receptor of pituitary inhibit LH and FSH

Androgen receptor antagonist

ResistanceClinical uses ALL

HL, NHLAdjuvant trt and for trrt of metastatic dzBreast ca. And endometrail ca.

Prostate ca. Leuprolide: prostate ca. Prostate ca.

Admin’Pharm-kineticssideefx *has the potential to cause

endometrial ca. Extra notes Mostly a antagonist and a

partial agonist for E receptors must have the receptor otwise doesn’t work

MICELLANEOUS drugs against ca.Cisplatin and Carboplatin Procarbazi

neL-Asparaginase IFN- Trastuzumab:

herceptinWhat is it? Cisplatin is a platinol

Carboplatin is a paraplatinol..Both alkylaing agents

Another alkylating agent

An enzyme (from bacteria)

Ab against HER2 protein

Mech of action Alkylate agents, bind to DNA Inhibit DNA/RNA syn

Deaminates asparagine aspartic acid… ca. Needs asparagine and takes it out of the pool of nutrition starvation

Unknown but Leukocytic

Ab ADCC via NK and monocytes

Clinical uses Solid tumors: testicular ca., ovarian ca

ALL Hairy cell leukemiaSquamous cell carcinomaMelanomaMM

Breast ca.

sideefx Vomiting after 1 hrKidney dysfx

BM depression

Good efx: low BM suppression and GI suppressionBad efx: hypersensitivity

Extra notes Extremely toxicTesticular ca. also use combo of vinblastine and bleomycinOvarian use with cyclophosphmideNeed to really hyrdrate the pt.Use corticosteroids and antiserotonin receptor against vomiting

Part of MOPP regimen for HL

Can use in combo with vincristine and prednisone

What is MOP??? Used in HL: mechlorethanimine, ONCOVIN, procarbazine, prednisone… now replaced by ABVDWhat is COP or CHOP? Used in NHL: cyclophosphamide, onceovin, prednisone, sometimes doxorubicinWhat is used for testicular ca? PVB platinol (hydration), vinblastine, bleomycin (cisplastin is replacedby etoposide sometimes)What is used for breast ca.? CMF cyclophosphamide, MTX, fleorouracil… sometimes tamoxifen