(alkylating agent - causes DNA cross-linking)

phenylalanine mustard used for multiple myeloma

(alkylating agent - causes DNA cross-linking)

estradiol linked to nitrogen mustard

mechanism: inhibition of microtubule formation 

treatment: prostrate cancer

(alkylating agent - causes DNA cross-linking)

substitutions of methyl group in nitrogen mustard causes decreased reactivity

mechanism:

 treatment: CLL

(alkylating agent - causes DNA cross-linking)

mechanism: prodrugs activated by P-450

side-effects: metabolite acrolein can accumulate in the bladder and cause hemorrhagic cystitis; give mesna to bind acrolein, used prophylactically

treatment: everything

(Nitrosoureas)

BCNU/carmustine

CCNU/lomustine

(alkylating agent - causes DNA cross-linking)

car mustang enters blood brain barrier treats brain tumors

mechanism: highly lipophilic 

(alkylating agent - causes DNA cross-linking)

"the thigh is close to the bladder"

intrathecally for carcinomatous meningitis

mechanism: lipophilic

(alkylating agent - causes DNA cross-linking)

colon cancer

(alkylating agent - causes DNA cross-linking)

"bus with the fan runs on a common lane and emits heavy smoke that you breathe in your mouth"

used orally in treatment of AML and CML 

side-effects: pulmonary fibrosis

(non-classic alkylating agent - polyfunctional alkylation)

"the pro car drives through DNA by Hodgkin and some one not related to Hodgkin"

Mechanism: causes chromatid and single strand DNA breaks inhibiting synthesis

Resistance: related to increase expression O6-alkylguanine-DNA alkyltransferase

(non-classic alkylating agent - polyfunctional alkylation)

"Dairy Car driven by neurologist Dr. Hodgkin carrying melons and meat"

mechanism: methylating DNA and causing direct DNA damage

Treatment: malignant melanoma, Hodgkin's, sarcomas, neuroblastoma, brain tumors

(non-classic alkylating agent - polyfunctional alkylation)

treat gliomas with good brain penetration

1. enzymatic detox by glutathione conjugation (GST)

2. increased repair by alkyltransferases or glycolyases (directly). O6-alkylguanine transferase, a kamikaze enzyme 

Toxicity:

Myelosuppression, Immunosuppression, Alopecia, Pulmonary fibrosis, leukemogenesis, infertility, hemorrhagic cystitis and SIADH

(carboplatin and oxaliplatin)

"cis-PLAAHT-in" (emesis)

used to treat testicular cancer (and bladder, ovary, lungs) 

mechanism: acts as alkylating agent covalently binds DNA and cross-links

side-effects:  emesis, renal toxicity (give diuretics),peripheral neuropathy and ototoxicity, myelosuppression

resistance: inc. gluthaione or augmented DNA repair

synthetic folate analog

Mechanism: enters cell and converted to polyglutamate (inc.retention in cell) inhibits DHFR (makes dihydrofolate into tetrahydrofolate) thus preventing purine synthesis

Side-effects: Down's susceptible to MTX toxicity

Leucovorin (reduced folate) rescue for overdose

Trimetrexate

Raltitrexed (Tomudex)

Lometrexol

Trimetraxate:lipophilic so it doesn't need folate carrier or polyglutamation by FPGS

 Treatment: P.carinii

Raltitrexed - highly selective inhibitor of thymidine synthetase

Lometrexol - highly polygluatmated specific inhibitor of purine synthesis

mechanism: synergistic with leucovorin in inhibiting Thymidylate synthase (converts UMP to dUMP)

Sensitivity: availability of PRPP and reduced folates as well as enzyme activities

Side-effects: dihydropyrimidine dehydrogenase (DPD) needed to clear 5-FU and deficiency leads to fatal toxicity

Treatment: Colorectal cancer

given orally and is converted to 5-FU by three enzymes

Treatment: refractory breast or colon cancer

Mechanism: prodrug, incorporation into DNA and blocks elongation and can also poison DNA Topoisomerase

Treatment: Leukemia and lymphoma

Side-Effects: myelosuppresion, nausea, and vomitting

Mechanism: prodrug, incorporated into DNA inhibiting synthesis and repair

Treatment: bladder cancer, pancreatic cancer, mesothelioma

Side-effects: Neutropenia, nausea, vomitting

Mechanism: hypoxanthine analog, incorporated into DNA as thiodeoxyguanosine and into RNA as 6MP ribose triphosphate

Treatment: ALL (6MP), AML (6TG)

Side-Effects: myelosuppression, immunosuppression, and hepatoxicity

 Mechanism: prodrug adenosine analog

Treatment: CLL, Hairy cell leukemia, and NHL

Side-Effects: myelosuppression

Mechanism: inhibits adenosine deaminase (ADA) accumulation of reactants toxic to lymphocytes

Side-effects: myelosuppression, nausea, vomitting, and neurotoxicity (somnolence, confusion, and coma)

Treatment: Hairy Cell, CLL, ATCLL, Waldestrom Macroglobulinemia

Mechanism: adenosine analog

just a more potent fludarabine with less non-hematologic toxicity

given orally

Mechanism: inhibitor of ribonucleotide reductase (critical stepin proliferating cells)

Treatment: CML 

Side-Effects: Myelosuppression

Resistance: increased expression of M2 subunit of RNP Reductase

"I am going to eat ALL ASParagus"

Mechanism: enzyme that depletes asparagine (many tumors cannot synthesize their own)

Treatment: ALL

Side-effects: Allergic reactions, decreased protein synthesis (hypoinsulinemia/hyperglycemia, reduced clotting factors/inhibitors), ASP (allergies, spare GI and bone marrow, and protein deficiency), cerebral dysfunction, pancreatitis

Anthracycline

Mechanism

1. DNA intercalation

2. Topoisomerase II interaction

3. Free radical formation

4. inhibition of helicase and causes altered signal transduction at cell membrane

Anthracycline

Pharmokinetics:

1. which one is oral?

2. distribution?

1. idarubicin, others unstable in acidic environment

 2. large volume of distribution, passive diffusion through transporters (lipophilic); pH will affect cellular localization

Anthracyclines

Drug Interactions

1. how to increase clearance?

2. how to increase metabolism?

3. inhibitors of P-gp ?

1. Heparin binds and forms insoluable aggregate increasing clearance of drug

2. drugs that increase hepatic microsomal enzyme activity (ie barbituates)

3.cyclosporine 

Anthracyclines

Toxicity

Non-cardiac: Extravasation causes local tissue damage and deep ulceration. Radiation recall may occur in skin, oral mucosa, lung, GI tract, and heart

Cardiac: protection with dexrazoxane probably by iron chelation therefore may increase myelosuppression and incidence of 2nd leukemias

Doxorubicin - pediatric

Duanomycin - acute leukemias

Idarubicin - oral , AML

Epirubicin -

Pirarubicin

mechanism: estrogen receptor antagonist in breast tissue but agonist in endometrial tissue

Treatment: breast cancer

side effect: endometrial cancer, DVT/PE, stroke, hot flashes, GI upset

Mechanism: Androgen receptor antagonist inhibiting binding of testosterone

Treatment: Prostate cancer

Other derivatives: bicalutamide, nilutamide

Mechanism: aromatase inhibitor, rate limiting in the synthesis of estradiol as well as gluccocorticoid synthesis...need to give concurrent glucocorticoids

Treatment: ER+ breast cancer

Side-effects: osteopenia, hot flashes, arthralgias

Let the goose go sever the line and let your production slide

Mechanism: GnRH agonists, initially stimulate FSH and LH secretion (clinical flare phenomenon) but steady levels causes downregulation of pituatary receptors for LH-RH thus inhibits estrogen and testosterone

Treatment: Prostate and Breast cancer

Mechanism: they cause differentiation of APML cells into neutrophils causing apoptosis

Treatment: APL

Mechanism: tumor cells have high conc. of glucocorticoid receptors and high doses of agonists lead to apoptosis

Treatment: B-cell malignancies (ALL, Multiple Myeloma, B-cell lymphoma)

Mechanism: Inhibits BCR-ABL tyrosine kinase and cKIT tyrosine kinase

Treatment: CML and GST (gastrointestinal stromal tumor)

Mechanism: HER2 tyrosine kinase inhibitor, monoclonal antibody to HER2 extracellular domain. works by eithe signal interference or immune mediated destruction

Treatment: Breast cancer

Mechanism: competitive inhibitor of HER2 and HER1 binding to ATP-binding pocket

Treatment: HER2+ Breast Cancer

Side Effects: Rash, diarrhea

Mechanism: given orally, inhibitors of EGFR

Treatment: Non small cell lung carcinoma

Side effects: rash

Mechanism: monoclonal antibody to EGFR

Treatment: breast and colon cancer

Mechanism: TKI targets VEGFR and PDGF-R

Treatment: renal cell carcinoma

Mechanism: TKI targeting VEGFR2, 3, cKIT, and RAF

treatment: RCC and may treat GIST

Mechanism: monoclonal antibody to VEGF, given by IV it reduces circulating levels of VEGF

Treatment: colon cancer, lung cancer, and breast cancer (needs to be used in combination; helps other drugs stay in tissue longer; prevents metastasis from small tumors)

Side Effects: Hypertension, pulmonary hemorrhage, and proteinuria

Mechanism: MTOR inhibitor (MTOR integrates signals from multiple pathways)

Treatment: RCC

Side-effects: hyperglycemia, hyperlipidemia, myelosuppression

Mechanism: anti-CD20 causes complement destruction (ADCC) or cell apoptosis

Treatment: NHL

Mechanism: human monoclonal antibody against CD33, linked with calicheamicin=smart bomb for myeloid lineage

Treatment: acute non-lymphocytic leukemia cell

Side effects: neutropenia, bone marrow suppression, etc.

Ytrium90 and Iodine 135 conjugated anti-CD20 antibody

Treatment: low grade (follicular) NHL resistant to Rituxumab

Mechanism: binds and inhibits 26S proteosome that is responsible for degrading ubiquitinated proteins

Treatment: Multiple Myeloma in combination with steroids

Side Effects: peripheral neuropathy, thrombocytopenia, GI Upset, asthenia

Mechanism: inhibits DNA methyltransferase (DNMT) leading to DNA hypomethylation

Treatment: myelodysplastic syndrome

Histone De-acetylase complex

mechanism: normal packaging of histones are de-acteylased (transcription repression depedent on HDAC) and transcription activation requires acetylation-but inhibition of HDAC can also have same effect

Treatment: cutaneous T-cell lymphoma 

Mechanisms: prevents chemo activation of chemoreceptor trigger zone and vomitting center in the brain

benzodiazepines (lorazepam)

antihistamines (diphenhydramine)

phenothiazine (prochlorperazine)

corticosteroids

cannabinoids (marijuana)

serotonin antagonists (ondansetron, granisetron)

Mechanism: anti-inflammatory activity and anti-angiogenic

Treatment: erythema nodosum, multiple myeloma

Side effects: sedation, constipation, and neuropathy