Anticancer Agents - Panavelil - Heme

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Definitions of Cell Cycle Specific drugs (CCS)

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-an antitumor agent that works selectively on tumor stem cells when they are passing through the cell cycle and NOT when they are in the Go, resting phase

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Cell Cycle Specific drugs (CCS)

Details

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-only stop at the DIVIDING STATE
-when a cell size is at 10^11 use these drugs to bring down the size and then hope the host can take the size down from there

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Definition of Cell Cycle Non-Specific drugs (CCNS)

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-an anticancer agent that acts on tumor stem cells when they are transversing the cell cycle as well as they are in the resting phase

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Cell Cycle Non-Specific drugs (CCNS)

Details

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-work better as initial agressive tx to reduce the size of the tumor and then add the CCS

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Antimetabolites

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-usually CCS
-required for DNA synthesis (do not allow the DNA to replicate)

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Vinca alkaloids and Taxanes

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-from tropical plant
-tx leukemias and SOLID tumors

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Alkylating agents

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CCNS

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Antineoplastic Abx

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-CCNS except 1 drug

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Signal Transduction Inhibitors (SDIs)

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-target things like tyrosine kinase
-b/c it is involved in oncogenic pathway activation (+ other kinases, MAP kinase, etc)

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****Log- Kill Hypothesis

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-concept was developed to define that anti-cancer drugs kill a fixed proportion of a tumor cell pop, NOT a fixed # of tumor cells
-1-log kill will eliminate a tumor pop by 90% and 10% of cancer cells remain

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Example of Log-Kill hypothesis:

3-log kill dose given to 10^12 cells

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-the result is 10^9 cells remaining
-this means 9.99x10^11 were killed

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Grow Fraction

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-the proportion of tumor cells that are actively dividing

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Rescue therapy

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-the administration of endogenous metabolites to counteract the effects of anticancer drugs on normal non-cancer cells

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***Recruitment Therapy

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-chemo process by which a CCNS drug is used to achieve a significant log kill followed by the use of a CCS drug to kill the cells that start dividing

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Antibiotics

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-usually CCNS, however there is an exception:
-Bleomycin is a CCS mixture glycopeptides that generate free radicals that bind to DNA and cause DNA nicks by an oxidative process

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Bleomycin

MOA

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-interacts w/ topoisomerase II enzyme and causes cells to accumulate in the G2 phase and mitosis
-(CYTOTOX depends on binding of Fe- bleomycin complex to DNA)

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Antibiotics (CCNS)

Resistance

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-INCREASED EFFLUX of drug
-DNA repair is also a resistance mechanism

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Bleomycin

Clinical application and AEs

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-squamous cell carcinoma/ Hodgkin's Lymphoma
-AEs: NOT myelosupressive (therefore, safe to give in combo w/ drugs that are toxic to bone marrow)
-Pulmonary toxicity is the MOST serious (pneumonitis which may lead to fibrosis and death)
-cardiotox is also common

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Dactinomycin (Act-D, DACT, Actinomycin D)

MOA

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-CCNS drug intercalates into the double helix between G-C base pairs of DNA, forming complex
-DNA-dependent RNA polymerase is non-fxnal on the DNA strands when complexed w/ the drug--> DNA can't unwind!

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****Dactinomycin (Act-D, DACT, Actinomycin D)

Resistance

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-Increased efflux (pump "tet A") of the abx from the cell via P-glycoprotein (solid)
-DNA repair is also another mech

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Dactinomycin (Act-D, DACT, Actinomycin D)

Clinical use and AEs

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-"multiple applications, Choriccacinoma (placental cancer)
-BM suppression (cancer drugs target EVERY cell, RBCs, thus need rescue
-also immunosup, n/v, diarrhea, stomatitis, alopecia

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Doxorubicin, daunorubicin, Idarubicin

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-another anthracycline abx
-aka Adriamycin (hydrolated analog of daunorubicin [cerubidine])
-part of "CHOP" therapy

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Doxorubicin, daunorubicin, Idarubicin

MOA

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-singlet or nascent O2 (free radical)
-reacts to anything...cuases the DNA strand to break

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What are the 3 major MOAs of anthracyclines?

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-all max active in S and G2 phases
1. Intercalation in the DNA
2. Membrane distruction
3. Oxygen free radicals through lipid peroxidation

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Doxorubicin, daunorubicin, Idarubicin

Clinical Use and AEs

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-multiple, ALL, ANLL, lymphomas, Hodgkin's lymphoma
-AEs: IRREVERSIBLE, dose dependent cardiotox (b/c of free radicals) also other toxicity and can lead to cardiomyopathy

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Dextrazoxane (ZineCARD)

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-CARD think cardiac chelator
-lowers the risk of developing anthracycline-induced cariomyopathy b/c it is a cyclic derivative of heavy metal chelator EDTA

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***What is Dextrazoxane (ZineCARD) been proven to do as far as pts w/ cardiac risks?

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-provide cardiac protection
-increase the cumulative dose of doxorubicin in pts w/ cardiac risks

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What are the alkylating agents?

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-CCNS drugs
-nitrogen mustards, nitroso-ureas (for CNS tumors), and alkyl sulfonates
***-dacocarbazine is also in this category and DECREASES TUMOR LOAD IN LEUKEMIAS

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Mechlorethamine (nitrogen mustard)

MOA

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-part of MOPP therapy
-bifunctional alkylating agent w/ 2 reactive groups
-drug loses a Cl- ion forms reactive intermediate that alkylates the G residue of DNA molecule--> cross-linkages that arrest enzymatic activities

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Mechlorethamine (nitrogen mustard)

***CLINICAL USES***

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-PRIMARILY Hodgkin's disease as part of the MOPP regimen
-also solid tumors, CML, CLL, NSCLC (non-small-cell lung cancer)

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Mechlorethamine (nitrogen mustard)

Resistance and AEs

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1. Resistance: dec perm of drug, increased conj w/ thiols such as glutathione, & poss inc DNA repair
2. AEs: GI distress, BM supp, immunosupp--> latent viral infx

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Cyclophosphamide (Cytoxan) and Ifosfamide (Ifex)

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-much like Mechlorethamine
-but taken orally, cytotoxic ONLY after generation of their alkylating species (following hydroxylation by cytochrome P450)

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Cyclophosphamide (Cytoxan) and Ifosfamide (Ifex)

MOA****

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-must undergo activation by mixed hepatic oxidase enzymes--> active compounds:
-phosphoramine mustard -reacts w/ DNA causing cytoxicity
-***TQ Acrolein- RENAL TOXIC, end result may be renal failure

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Cyclophosphamide (Cytoxan) and Ifosfamide (Ifex)

Resistance and Clinical Uses

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-increased DNA repair, decreased drug perm, rxn w/ thiols
-Multiple uses, ovarian cancers

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Cyclophosphamide (Cytoxan) and Ifosfamide (Ifex)

***AEs

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-most prominent is BM depression, then alopecia, n/v
-hemorrhagic cystitis***
-adeq hydration as well as IV injection of MESNA (thioester bonds w/ acroleum) which inactivates the toxic compounds can minimize this problem

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Cyclophosphamide (Cytoxan) and Ifosfamide (Ifex)

AEs - Malignancy

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-secondary malignancies including bladder carcinoma may appear years after therapy so make sure to watch for them

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***Nitrosos-Ureas

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-***CROSS BBB
-BiCNU
-tx solid tumors of the brain
-diabetogenic and can cause REVERSIBLE renal damage

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Nitrosos-Ureas

MOA

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-decompose to reactive alkylating metabs and isocyanate compounds, cause cross links if DNA to inhib replication
-cytotoxicity is expressed ONLY on cell division

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***Nitrosos-Ureas

Clinical Use

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-PENETRATE the CNS
-mostly for brain tumors (solid tumors)
-also for HD and NHL

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Nitrosos-Ureas

AEs

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-include delayed hematopoitic depression and CNS depression
-renal toxicity and pulmonary fibrosis

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***Busulfan

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-well absorbed ORALLY/hep metab
-LOW DOSE- selective supp of granulocytopoiesis leading to use in most regimens of CML
-TQ: what are selective for myeloid tumors? A: BUSULFAN

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*Melphalen

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-taken orally, CCNS
-for MULTiPLE MYELOMA (does not cure but increases the life expectancy by 4 years)
-breast, testicular, ovarian, NHL