Cancer chemotherapy

Question 1

When are drugs more effective?

Answer 1

Drugs are more effective when a large proportion of tumor cell are proliferating.

High growth fraction.

Question 2

Advantages and Disadvantage of using CCNS drugs

Answer 2

ADVANTAGES

They have a broad activity
Effective in slow-growing tumors
- Because they also target non-
specific dividing cells.

DISADVANTAGE

Increased Toxicity
- non-specific nature
- Can cause damage to normal cell
as well
Resistance

Question 2

Cell Cycle Non-Specific drugs (CCNS)

Answer 2

Drugs that act on cancer cell in all phases. Including G0

Can kill both dividing and non-dividing cell.

Question 2

S-phase Specific drugs

Answer 2

Antimetabolites

1. Methrotrexate
2. Fluorouracil
3. Mercaptopurine

Question 3

Examples of Cell cycle non-specific drugs.

Answer 3

1. Alkalylation Agents
   
   • Cyclophosphamide
   • Cisplatin
   • Lomustine
   • Carmustine
2. Antitumor antibiotics.
   
   • Doxorubicin
   • Bleomycin
   • Mitomycin

Question 3

General adverse effect of antineoplastic drugs ( Cancer drugs)

Answer 3

1. Nausea/vomiting
2. Alopecia= loss hair
3. Myelosuppression= bone marrow loss
4. Low WBC= Decrease immunity
5. Ulceration of the mouth and IG
6. Increase serum uric acid= increase risk of gout
7. Secondary cancers= many cancer drugs mutate the DNA and can lead to another cancer.

Question 3

Cell Cycle Specific Drugs (CCS)

Answer 3

They act on cancer cell during a specific phase of cell cycle.

S-phase, M-phase, G2 phase

Target in DIVIDING cells

Most effective agains the rapidly growing tumors.

Question 3

Advantage and Disadvantage of cell cycle specific drug

Answer 3

ADVANTAGES

-Target action
-Fewer side effect on non-dividing cell

DISADVANTAGE

-Less effective on slow-growing tumor
-Toxicity on rapidly dividing normal cell. Like hair loss, GI symptoms, Myelosuppression.

Question 4

M-phase Specific drugs

Answer 4

Microtubule inhibitors

Vinca Alkaloids
1. Vincristine
2. Vinblastine

Taxanes
1. Paclitaxel
2. Docetaxel

Question 4

G2 phase Specific drugs

Answer 4

Toposiomerase II inhibitors
1. Etoposide
2. Teniposide
3. Irinotecan
4. Topotecan

Bleomycin

Question 5

Tumor lysis syndrome

Answer 5

The anti cancer drug is causing this.

Occur when a large number of cancer cell die in response to therapy within a short period, releasing their content into the blood.

We can give Allopurinol to inhibit Xanthine Oxidase.

Rasburicase can inhibit Uric acid to Allantoin

Characteristics finding:
- Hyperuricemia
-Hyperkalecemia
-Hyperphosphatemia
- Hypocalcemia

Question 6

Log-kill hypothesis

Answer 6

Chemotherapy drugs kill a constant fraction of tumor cell, rather than a constant number.

Initial treatment may reduce the tumor size but not eliminate it. We need multiple treatment cycles. Each cycle kills a fraction of the remaining cells. But the remain cell may become resistance over time

Role of combination therapy

Question 7

Combination therapy

Answer 7

Optimizing therapeutic efficacy while minimizing toxicity.

Combining Drugs that act on different phases of the cell cycle.

Minimize resistance: Different mechanism of action. If some drugs are resistance to one drug they might be to the other one.

Non- overlapping Toxicities.

Question 8

Primary induction chemotherapy

Answer 8

Primary treatment
Palliation- Relief of symptoms and suffering caused by cancer
extended time of tumor progression.

Question 9

Neoadjuvant chemotherapy

Answer 9

Reduce the tumor size for better surgical outcome

Question 10

Adjuvant chemotherapy

Answer 10

Procedure following after surgical procedure. To reduces risk of local and systemic recurrence.

Question 11

Alkylating Agents

Answer 11

Are non-specific drugs

Alkalynation of nucleophilic group on DNA bases especially N-7 position of guanine.

Causes-
1. Cross linking of bases
2. Abnormal base pairing
3. DNA strand breakage.

Question 12

Cyclophosphamide

Answer 12

Alkylating agent- non specific drug

• is a pro drug
• Hepatic cytochrome P450 enzyme converts it to its active metabolite ( phosphoramide mustard)
• Metabolite called Acroline that causes Hemorrhagic cystitis*. This can be reduced by Mesna.
• Also Cause SIADH

Question 13

Mechlorethamine

Answer 13

Alkylating agent- non specific drug

Converts in the body to a reactive cytotoxic product.

Toxicity:
1. GI distress
2. Alopecia
3. Myelosupression
4. Sterility
5. Vesicant (blisters)

Question 14

Procarbazine

Answer 14

Alkylating agent- non specific drug

Forms hydrogen peroxide, which generates DNA-damaging free radicals

Toxicity
1. GI distress
2. Myelosuppression
3. CNS dysfunction
4. Leukemogenic
5. Disulfiram like reaction ( is like the drug they give to alcoholics to stop drinking)
6. Inhibit monoamine oxidase (MAO)

Question 15

Dacarbazine

Answer 15

Alkylating agent- non specific drug

Clinical use for Hodgkins lymphoma
(Epstein-Barr virus)

toxicity
1. GI distress
2. Alopecia

Question 16

Carmustine and Lomustine

Answer 16

Alkylating agent- non specific drug

Nitrosoureas

Highly lipid soluble: Can cross BBB

DNA alkylation: cross linking

Useful for treatment of CNS cancer

Question 17

Temozomide

Answer 17

Penetrates the CNS

Clinical use for
1. Anaplastic astrocytoma (brain tumor) refractory to nitrosoureas
2. Glioblastoma

Question 18

Busulfan

Answer 18

Alkylating agent- non specific drug

Very important one

DNA alkylation: cross-linking

Clinical use:
1. Chronic myelogenous leukemia

Toxicity:
1. Skin pigmentation
2. Adrenal Insufficiency*
3. Pulmonary fibrosis*

Question 19

Cisplatin Carboplatin Oxaliplatin

Answer 19

Alkylating agent- non specific drug Platinum Analogs Platinum atoms binds to DNA bases Croslinks DNA Toxicity of Cisplatin and Carboplatin 1. GI distress- Severe nauseas and vomiting* 2. Nephrotoxicity* ( can be reduced by using mannitol with severe hydration) Toxicity of Oxaliplatin Neurotoxicity* But do NOT give nephrotoxicity

Question 20

Antimetabolites

Answer 20

Cell specific drugs acting on S-phase They have immunosuppressant action Folic acid blocker- Methotrexate Purine- Mercaptopurine and Thioguanine Pyrimidines- Fluorouracil, Cytarabine and Gemcitabine

Question 21

Methrotrexate (MTX)

Answer 21

Antimetabolite- S phase Binds with high affinity to active catalytic site of Dihydrofolate Reductase and inhibits it *. - Decrease the synthesis of thymidylate (dTMP), purine, pyrimidine and amino acids - Interfere with protein metabolism Resistance 1. Reduced drug accumulation 2. Changes in enzyme sensitivity/activity 3. Reduced formation of polyglutamate Clinical uses: 1. Choriocarcinoma 2. acute leukemias 3. solid tumor 4. ectopic pregnancy 5. Rheumatoid arthritis 6. psoriasis Toxicity- 1. Bone marrow suppression* 2. mucositis 3. Hepatotoxicity * Leucovorin reduces the toxic effect of methotrexate on normal cell.

Question 22

Mercaptopurine (6-MP) and Thioguanine (6-TG)

Answer 22

Purine Antimetabolites Activation by HGPRTases* inhibition of enzymes in purine metabolism. Metabolism of 6-MP by xanthine oxidase is inhibit by Allopurinol and Febuxostat ** Clinical use: Acute leukemia, chronic myelocytic leukemia Toxicity: bone suppression and hepatic dysfunction.

Question 23

Cladribine

Answer 23

Purine antimetabolites Converted to Cladribine triphosphate Incorporated into the DNA and causes strands breakage and kills T cell.

Question 24

Fluorouracil (5-FU)

Answer 24

Pyrimidine Antimetabolites 5-FU is converted into 5-FdUMP 5-FdUMP inhibits Thymidylate synthase* and inhibit DNA synthesis Another metabolite called FUTP Interferes with RNA function. Clinical uses: 1. Bladder, breast, colon and ovarian cancer 2. Topically for Keratoses and basal cell carcinoma. Resistance: Increased Thymidylate synthase activity ( basically is more than the drug) Toxicity: Neurotoxicity (hand-foot syndrome) Give them a dose of thymidine*

Question 25

Cytarabine

Answer 25

Pyrimidine Antimetabolites Convert to AraCTP- inhibits DNA polymerases*

Question 26

Gemcitabine

Answer 26

Deoxycitytidine analog Metabolite Gemcitabine diphosphate- inhibits ribonucleotide reductase - inhibit DNA synthase.

Question 27

Vinca Alkaloids

Answer 27

Plant-base drug Works on M phase 1. Vinblastine 2. Vincristine 3. Vinorelbine Prevents assembly of tubulin dimers into microtubules. Block mitotic formation. * Toxicity: Neurotoxic * "glove and stocking" neuropathy Clinical Vinblastine and Vincristine- acute leukemias lymphomas Vinorelbine- nonsmall cell lung cancer and breast cancer.

Question 28

Taxanes

Answer 28

Pland-based drug - M phase cannot progress to Anaphase. 1. Paclitaxel 2. Docetaxel Prevent the microtubule from disassembly into tubulin monomers. Interfere with mitotic spindle. Hyperstabilize microtubules in M phase. Toxicity: Paclitaxel- Peripheral neuropathy "glove and stocking"* (same as Vinca) Docetaxel- Neurotoxicity*

Question 29

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