Anti-Cancer Drugs: Alkalyting Agents Flashcards Preview

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The next set of drugs to cover are the Alkylating Agents. What is the MOA of these drugs?

Alkylations of DNA within the nucleus represent the major interactions that lead to cell death
--major site of alkylation within DNA is the N7 position of guanine
These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alkylating agents are bifunctional, with two reactive groups. Alkylation of guanine can result in miscoding through: abnormal base pairing with thymine and depurination by excision of guanine residues which leads to DNA strand breakage through scission of the sugar phosphate backbone of DNA


What kind of cells are most susceptible to Alkylating agents?

Replicating cells
--in the late G1 and S phases of the cell cycle


What is the mechanism of resistance of Alkylating agents?

1. Increased capability to repair DNA lesions through increased expression and activity of DNA repair enzymes.
2. Decreased transport of the alkylating drug into the cell.
3. increased expression or activity of glutathione and gluthathione associated proteins, which are needed to conjugate the alkylating agent or glutathione S transferase activity, which catalyzes the conjugation.


What are the adverse effects of Alkylating agents?

Dose related and occur in rapidly growing tissues (bone marrow)
N/V: pre treat with 5-HT3 receptor antagonists (ondansetron)
Potent Vesicants and can damage tissues at the site of administration as well as produce systemic toxicity
Carcinogenic (secondary malignancies) -- AML


Alkylating agents are divided into different classes:

1. Nitrogen Mustards:
--cyclophosphamide, Ifosfamide, Mechlorethamine, Melphalan
2. Nitrosoureas:
--Carmustine and Lomustine
3. Alkyl Sulfonates:
4. Methylhydrazines:
5. Triazines:
--Dacarbazine (DTIC)


Lets discuss each drug within the Alkylating classes individually. First up are the Nitrogen Mustards. The first drug to discuss in this class is cyclophosphamide. What are the pharmacokinetics?

Oral or IV routes with equal clinical efficacy
Activated by P450 (CYP2A6,2B6,3A4,3A5,2C9,2C18,2C19 with 2B6 displaying the highest 4 hydroxylase activity. These active metabolites are delivered to both tumor and normal tissue, where non-enzymatic cleavage of aldophoshpamide to cytotoxic forms phosphoramide mustard and acrolein occurs.
Liver is protected through enzymatic formation of the inactive metabolites


What are the clinical applications and AE of cyclophosphamide?

--breast, ovarian, non hodgkins lymphoma, CLL, soft tissue sarcoma, neuroblastoma, Wilm's tumor and rhabdomyosarcoma
--NV, bone marrow suppression (pancytopenia)
--hemorrhagic cystitis: Acrolein is responsible for the hemorrhagic cystitis!! Can be prevented by parenteral administration of Mesna


Moving on to the next Nitrogen Mustard Alkylating Agent is Ifosfamide. What are the PK and Adverse effects?

--analog of cyclophosphamide
--Prodrug (activated by CYP450 3A4)
--Bone marrow depression
--Nephrotoxicity, Hemorrhagic cystitis and alopecia
(give Mesna for the cystitis)
Greater extent of side effects than cyclophosphamide


The third Nitrogen Mustard Alkylating Agent is Mechlorethamine. What are the PK, Clinical and AE?

--powerful vesicant (IV)
--drug not excreted
--Hodgkins Lymphoma
--severe bone marrow depression and n/v


The fourth and final Nitrogen Mustard Alkylating Agent is Melphalan. What are the AE and clinical applications?

--Bone marrow suppression, hepatotoxicity, pulmonary fibrosis
Multiple Myeloma


The next class of Alkylating Agents are the Nitrosoureas (carmustine and lomustine) , what are the PK of this class of drugs?

Carmustine = IV
Lomustine = oral
--both require biotransformation, which occurs by nonenzymatic decomposition, or metabolites with both alkylating and carbamoylating activities.
Urinary excretion


What are the clinical applications, AE and resistance for the nitrosoureas?

--Brain Tumors (Cross BBB)
--myelosuppression, renal failure, pulmonary fibrosis
--non cross resistant with other alkylating agents


Third class of Alkylating Agents are the Alkyl Sufonates, which includes Busulfan. What are the clinical applications and AE?

---chronic Myelogenous Leukemia
---N/V, Bone Marrow suppression and Pulmonary Fibrosis


The fourth class of Alkylating agents are the Methylhydrazines, which include Procarbazine, what are the clinical applications, PK and AE?

---Hodgkins and Non-Hodgkins
--Brain Tumors
--One metabolite is a weak monoaminse oxidase (MAO) inhibitor and adverse events can occur when procarbazine is given with other MAO inhibitors as well as sympathomimetic agents and tyramine containing foods.
Carcinogenic potential is higher


The fifth and final class of Alkylating Agents are the Triazines, which include Dacarbazine (DTIC). What are the PK, Clinical and AE?

--Potent Vesicant
--Malignant melanoma, Hodgkins Lymphoma, Soft Tissue Sarcoma and Neuroblastoma
--Myelosuppression and N/V


Moving on to the next set of drugs are the Platinum Coordination Complexes. What are some features of these drugs?

Covalently bind to DNA
Broad Anti-neoplastic activity and have become the foundation for tx of testicular cancer, ovarian cancer, and cancers of the head/neck, bladder, esophagus, lung and colon.


First drug up for the Platinum Coordination Complexes is Cisplatin. What is the MOA, USES and AE?

--kills cell in all stages of cell cycle, inhibits DNA synthesis and binds DNA through formation of cross links
--Testicular, Ovarian, Bladder
Use with vinblastine and bleomycin: curative therapy for nonseminomatous testicular cancers
--Ototoxicity, Peripheral Neuropathy, Nephrotoxicity (pretreat with hydration and diuresis)
--Amifostine is a thiophosphate cytoprotective agents to reduce risk of renal toxicity


The second drug within the class of Platinum Coordination Complexes is Carboplatin. What are some features?

Analog of Cisplatin
Ovarian Carcinoma
Less nausea, neurotoxicity, ototoxicity, and nephrotoxicity than cisplatin
Dose limited by myelosuppression


Moving on to the next class of Anti-cancer drugs are Hormonal Agents. This includes what?

1. Glucocorticoids
2. Estrogen Inhibitors:
--selective estrogen receptor modulators (SERMs): tamoxifen and raloxifene
--selective estrogen receptor downregulators (SERDs): Fulvestrant
--Aromatase Inhibitors: Anastrozole, Letrozole and Exemestane
3. Androgen Inhibitors:
--Gonadotropin Releasing Hormone Analogs: Goserelin and Leuprolide
4. Androgen Receptor Blockers:


Now lets go through each of these Hormonal Agents. First up are the Glucocorticoids, Prednisone. What are some features?

Induces Lymphocyte Apoptosis
--used against ALL, Lymphoma and Multiple Myeloma
Used in management of autoimmune hemolytic anemia and thrombocytopenia associated CLL because it increases the number of platelets and RBCs


Moving on to the next Hormonal Agents are the Estrogen Inhibitors. First up are the Selective estrogen receptor modulators (SERMS). What is their action?

Bind to and active or block estrogen receptors depending on the target tissue


There are two drugs in the selective estrogen receptor modulators (SERMS). First up is Tamoxifen, what are some features?

Anti-estrogen effect at the breast
Acts as estrogen receptors agonist at endometrium and bone
Prevention and Tx of Breast Cancer
AE: hot flushes, nv, fluid retention, thromboembolic events and endometrial hyperplasia


The second drug in the selective estrogen receptor modulators (SERMs) is Raloxifene. What are some features?

Estrogen antagonist at the breast and endometrium
Estrogen agonist effect at bone
Prevention of postmenopausal osteoporosis
Prophylaxis of breast cancer in high risk postmenopausal women
Thromboembolic events


Moving on with the Hormonal Agents are the Estrogen Inhibitors. 2nd up are the selective estrogen receptor downregulators (SERDs). The drug in this category is Fulvestrant. What are some features?

Pure estrogen receptor antagonist with no agonist activity
Binds to and inhibits estrogen receptors (ER) dimerization
Increased ER degradation
Reduces the number of ER molecules in cells
Used in tamoxifen resistant breast cancer


Finally within the Estrogen Inhibitors Hormonal Agents are the Aromatase Inhibitors. Which are Anastrozole, Letrozole, and Exemestane. What are features of these drugs?

Inhibit aromatase enzyme: needed for estrone synthesis from androstenedione
Estrone is the primary estrogen is postmenopausal women
Used as Adjuvant chemotherapy in estrogen receptor positive breast cancer
Anastrozole and Letrozole are nonsteroidal competitive (reversible) inhibitor of aromatase
Exemestane is a steroidal and irreversible inhibitor of aromatase


Next up in the Hormonal Agents are the Androgen Inhibitors: First is the Androgen Receptor Blocker, Flutamide. What are some features?

Non steroid, competitive antagonist at the androgen receptor
Tx prostatic carcinoma
Frequently causes mild gynecomastia
Reversible hepatic toxicity


Next in the Androgen Inhibitors are the Gonadotropin releasing hormone analogs -- Goserelin and Leuprolide. What are features?

1. Pulsatile administration stimulates FSH and LH release from anterior pituitary
2. Continuous Administration produces a biphasic response:
--initial phase (Flare): during first 7-10 days of continuous GnRH analogs administration (increased concentrations of gonadal hormones production). Can be counteracted with concurrent admin of Flutamide for 2-4 weeks
--delayed phase: continuous presence of GnRH analogs results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids. Inhibitory action is due to a combination of receptor down regulation and changes in the signaling pathways activated by GnRH


What are uses of continuous administration of GnRH analogs?

Prostate Cancer
--cause impotence, hot flashes and testicular atrophy

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