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Cancer Pharmacology

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Which cancers may be cured by chemotherapy?
<10 % of advanced cancers are cure d by chemo and inverse relationship between # of cancer cells and curability

1) Acute leukemia (AML, ALL)
2) Hodgkin's and non-Hodgkin's lymphoma
3) Germ cell cancer
4) Choriocarcinoma
5) Small cell lung cancer
Describe the Gompertzian model of tumor growth.
Described the growth kinetics of solid tumors

- Growth fraction of tumor is not constant but decreases exponentially with time (peaks at 37% of final size)
- Explains why advanced cancers (with low growth fractions) are less responsive to therapy.

**Opposite to what is observed with exponential kinetics in L1210 murine leukemia system.
What is the basic cell division process of a cancer cell?
Same as usual cells (4 phases)
Growth fraction= fraction of cells in cell cycle (NOT in Go)

1) M phase- mitosis and cell division, 2%

2) S phase- DNA synthesis, 35%

3) G1-phase- Longest phase, RNA/protein and cell growth, 40-45%

4) G2- phase- Specialized proteins in preparation for mitosis, 15-20%
What are the basic cell-cycle-specific anti-cancer agents?
1) Antimetabolite (S-phase)
- MTX (dihyrofolate reductase inhibitor)
- 5-FU
- 6-MP
- Gemcitabine
- Hyroxyurea

2) Vinca alkaloids (M-phase)
- Vincristine
- Vinblastine
- Vinorelbine

3) Taxanes (M-phase)
- Paclitaxel

4) Etoposite (G2-M) (Topo II inhibitor)

5) Bleomycin (G2-M)
What are the current major limitations of cancer chemotherapy?
2 biggest are NARROW TI resulting in toxicity and rapid drug resistance development (depends on inherent genetic instability)

1) Clinical Assay system (FFP, RFS, OS) is inadequate

2) Inability to:
- determine metastasis
- detect minimal residual disease
- explore dose-response curve
- minor impact of drug on individual cancer cells in vivo.

3) Specificity

4) Drug delivery

5) Drug resistance
What are basic mechanisms of intrinsic and extrinsic cellular drug resistance?
1) Intrinsic (Goldie-Coldman Hypothesis)

- Tumor cells mutate to drug resistance at a rate intrinsic to the genetic instability of a given tumor
- Loss of checkpoint control

2) Acquired
- Decreased intracellular drug level (increased drug efflux and decreased inward transport)
- Increased drug inactivation
- Decreased conversion of drug to active form.
True or False:

Normal dividing tissues never become resistant to the cytotoxic effects of chemotherapy.
What is the only current cancer-speciic target for therapy?
BCR-ABL tyrosine kinase expressed by CML cells.
The following are all cancers that can be cured with chemotherapy EXCEPT:

1) Non Small Cell Lung Cancer
2) Germ Cell Cancer
3) Choriocarcinoma
4) Acute Leukemia
1: Chemotherapy can be delivered alone or in conjunction with radiation therapy or surgery. Once non-small cell lung cancer (NSCLC) becomes disseminated chemotherapy is used for palliative purposes only. However, in patients with early stage disease the addition of chemotherapy to the other treatment modalities indicated previously may result in higher cure rate.
The following regarding cell cycle is correct EXCEPT:

1) G2 phase - Interval during which the formation of specialized proteins in preparation for mitosis occurs.

2) S Phase - Time during which DNa is synthesized

3) M phase - Period of mitosis / Cell division

4) G1 phase - This is the shortest phase and is time when RNa synthesis and cellular grown occurs.
4: Longest
What are the major Anti-metabolite anti-cancer agents and how do they work?
Most active in S-phase of cell cycle, when DNA is being synthesized

All require metabolism, often to di- and tri-phosphorylated forms
1) Anti-folates
- Methotrexate
- Pemetrexed
- Pralatrexate

2) Fluoropyrimidines
- 5-FU
- Capacitabine

3) Deoxycytidine analogs
- Cytarabine (ara-C)
- Gemcitabine

4) Purine analogs
- 6-MP
- 6-Thioguanine
- Fludarabine
- Cladribine
- Clofarabine
- Nelarabine
Which anti-metabolic drug is described by each of the following mechanisms?

1) Binds catalytic site of dihydrofolate reductase and interferes with THF synthesis

2) Acts during S phase, inhibiting thymidylate synthase

3) Di-phosphate form inhibits ribonucleotide reductase, while tri-phosphate form inhibits DNA POLI-a and -b

4) Anti-DNA synthesis and pro-apoptosis associated with, immunosuppression and opportunistic infections

5) Purine nucleoside analog that targets lymphoid cells and, once di- and tri-phosphorylated, can inhibit DNA polymerase a and b, as well as incorporating into DNA
1) MTX (THF acts as one-carbon carrier for enzymatic processes involved in methionine and purine synthesis)

2) Pemetrexed (pyrolopyrimidine antifolate analog) used in combination with Cisplatin for Mesothelioma and non-small cell lung cancer.

3) Gemcitabine (Deoxycytidine analog) used in a wide variety of cancers (Unlike Cytarabine, which is ONLY hematological)

4) Fludarabine (purine analog used in CLL and non-hodkins lymphoma)

5) Cladribine (purine analog used in hairly cell leukemia)
How does MTX selectively act on cancer cells and how normal cells be further protected during MTX treatment?
Watch out for mucositis, diarrhea, myelosuppression and neurotoxicity at high doses!

1) MTX Inhibits DHFR in cancer cells because its polyglutamate form (FPGS-mediated) is selectively retained in cancer cells

2) Reduced folate Leucovorin is a rescue compound that can be co-administered with high-dose MTX to protect normal cells.
What are the similarities between all anti-folate cancer agents?
MTX, Pemetrexad and Pralatrexate are all

1) transported into cells via the reduced folate carrier (RFC)

2) activated by FPGS to polyglutamate forms, which are retained in cancer cell.

3) Adjusted in the case of renal dysfunction

4) Inhibit DHFR, Thymidylate synthase or some combination of the 2, preventing purine and thymydilate synthesis.

5) Require B12/folate supplementation
What are the 2 major Deoxycytidine analogs and how do they work to treat cancer?
Both Cytarabine and Gemcitabine become phosphorylated by deoxycytidine kinase and then further phosphorylated to active forms.

1) Cytarabine (continous infusion in HEMATOLOGICAL cancers ONLY)

- S-phase antimetabolite converted by deoxycytidine kinase to 5'-mononucleotide (ara-CMP), which is converted to ara-CTP.

- ara-CTP competitively inhibits DNA POLI-alpha (DNA synthesis) and beta (repair)

2) Gemcitabine (wide range of cancers)
- Flourine-substituted deoxycytidine analog phosphorylated by deoxycytidine kinase to monophosphate form, and then to di- and tri-phosphate forms.

- Di-phosphate form inhibits ribonucleotide reductase
- Tri-phosphate form inhibits POLI-a and POLI-b
- Incorporates into DNA
- Can cause flu-like symptoms are rarely HUS or TTP
What are the 3 major types of purine analogs and how are they used in anti-cancer therapy?
1) 6-Thiopurines
- Must be metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to produce active compound.

- 6-MP (childhood acute leukemia) and 6-TG (adult acute leukemia) inhibit enzymes in de novo purine synthesis

2) Fludarabine

3) Cladribine
Why must 6-MP dose be reduced in the presence of Allopurinol?
Allopurinol is a purine analog that inhibits Xanthine Oxidase, the enzyme which is also responsible for inactivating 6-MP to 6-thiouric acid.

6-TG, on the other hand is deactivated through deamination, and is not a worry with gout treatment.
What are the most common side effects of all anti-metabolite drugs?
1) Bone marrow suppression with neutropenia

2) GI- diarrhea, mucositis, nausea/vomiting

3) Derm- hand-foot syndrome

4) Neuro

5) Immunosuppression.
What is "dihydropyrmidine dehydrogenase (DPG) deficiency" and how does it relate to anti-cancer drug metabolism?
DPD is important for the catabolism of 5-FU, and can lead to toxic accumulation.

Similar to 6-Thiopurine methyltransferase (TPMT) deficiency, where 6-MP and 6-TG build up.
Which anti-metabolite drugs have activity against hematologic cancers, solid cancers or both?
1) Hematologic ONLY
- Deoxycytidine, Cytarabine (AML and Hodkin's and non-Hodkins, lymphoma)

2) Solid ONLY
- Fluoropyrimidine, 5-FU and pro-drug Capecitabine (colorectal, gestational, osteogenic sarcoma)

- Deoxycytidine analog, Gemcitabine

What types of cancers are sensitive to the different types of purine analogs?
1) 6-MP and 6-TG
- Acute leukemias

2) Fludarabine and Cladribine
- Low-grade, non-Hodgkin's lymhoma
- Hairy cell leukemia
How does 5-FU target solid cancers?
(Like pro-drug, Capcetibine), Pyrimidine analog that irreversibly inhibits thymidylate synthase

**Thymidylate synthase generates thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair**
How do Anthracyclines exert cytotoxic effects in anti-cancer treatment?
Cell-cycle-independent, Antibiotics isolated from Streptomyces that are given IV and hepatically metabolized (Daunorubicin for AML and Doxorubucin for more broad effect)

**Dose-limited by Myelosuppression**

4 Mechanisms (TOPO, Radicals, DNA-binding and Membrane-binding)

1) Anti-topoisomerase II (double-cut repair)

2) Semiquinone free radicals and oxygen-free radicals

3) Binding to DNA through intercalation

4) BInd to membranes and alter fluidity-transport
Which of the following regarding Anthracycline anti-cancer agents is false?

1) Dose-limited by myelosupression with neutropenia and sometimes cardiotoxicity

2) Inhibit topoisomerase II and bind to lipid membranes

3) Renal metabolism

4) Given IV, often in combination

5) Can produce "radiation recall reactions" with erythema and desquamation at sites of prior radiation.
3- They are hepatically metabolized

These antibiotics are given IV, often in combination and can cause radiation recall, cardiotoxicity and myelosupression.
What are the major alkylating agents and how do they work?
1) Cyclophosphamide (HIGH oral bioavailability), Mechlorethamine, Melphalan and Chlorambucil

2) Transfer alkyl groups to DNA in nucleus at N7 position of guanine (as well as others)

**resistance occurs when repair mechanisms ramp up and/or glutatione increases and inactivates drugs**
Why are Nitrosourea compounds useful in treating brain tumors?
These drugs require non-enzymatic decomposition for activation, and they act through akylation and carbamoylation.

They are HIGHLY lipid-soluble.
How does Etoposite (VP-16) work to treat Hodgkin's and non-Hodgkin's lymphomas?
Semi-synthetic Topoisomerase inhibitor that also hits solid tumors.
How do each of the following agents treat cancer?

1) Vinblastine

2) Vincristine

3) Rituximab

4) Imatinib

5) Cyclophosphamide
1) Vinca alkaloids bind tubulin and prevent polymerization of tubulin dimers, disturbing M phase (hepatic metabolism)

2) Same as 1, but worry of Neurotoxicity>>>Myelopsupression

3) Anti-CD20 on B cell, non-Hdkin's lymphoma and leukemia

4) Antibody against Bcr-Abl tyrosine kinase domain in CML.....t(9:22) that produces fusion protein

5) Alkylating agent with high oral bioavailability
Which anti-cancer drugs are cell cycle independent?

Which ones are not?
Anthracycline antibiotics, Alkylating agents, Rituximab, Imatinib

Anti-metabolites hit S phase
Vinca alkaloids hit M-phase (tubulin polymerization)
Dose limiting features of anthracyclines includes all of the following EXCEPT:

1) Neutropenia
2) Cardiotoxicity
3) Paraesthesias
4) Arrhythmias
All of the following are Alkylating agents apart from:

1) Ifosfamide
2) Cyclophosphamide
3) Busulphan
4) Idarubicin
5) Melphalan
Regarding the mechanism of action of alkylating agents, which of the following is correct?

1) Alkylation of the RNA
2) Cross-linking of DNA
3) Inhibition of microtubules
4) Inhibition of topoisomerase I
5) Alkylation of thymine can result in miscoding via abnormal base pairs
Regarding Etoposide, which of the following is true:

1) Is used to treat acute leukemia
2) The oral bioavailability is about 50% , so oral dose is twice the IV dose
3) Inhibits topoisomerase I and so resulting in DNA damage
4) Dose reduction is not required in renal dysfunction
Main dose limiting side effect of Vinblastine is:

1) Peripheral Neuropathy
2) Urinary retention
3) Nausea and Vomitting
4) Bone marrow suppression
5) Constipation

This is in contrast to the similar “spindle poison” called vincristine. The dose limiting toxicity associated with vincristine when administered at recommended dose is peripheral and autonomic neuropathies.
Rituximab has been used in treatment of many different hematological malignancies and disorders. From the list below, identify 2 disorders that are NOT treated by Rituximab

1) TTP
2) Diffuse Large B cell Lymphoma – CD 20 negative
3) ITP
4) Diffuse large B cell lymphoma – CD 20 positive
5) Post transplant lymphoproliferative disorder
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