Brain Tumor Pharmacology

Question 1

List some of the pharmacokinetic reasons why tumors of the brain are hard to treat.

Answer 1

• inability of the drug to pass across the BBB

- common overexpression of P-gp by tumors in the brain

Question 2

What is an example of pharmacodynamic mechanisms of resistance that brain tumors have against chemotherapy?

Answer 2

gap junctions between astrocytes and tumor cells allow for communication and upregulation of genes that promote tumor cell survival.

Question 3

Why is the “survival signal” passed from astrocytes to tumor cells significant for therapy of brain tumors?

Answer 3

that even if the drug overcomes the pharmacokinetic barriers and reaches the tumor, it may not be able to work as effectively as it would in the periphery

Question 4

What are the three main chemotherapeutic agents used in the treatment of brin tumors?

Answer 4

carmustine, lomustine, and temozolomide

Question 5

What is a commonality in all of the drugs use to treat brain tumors?

Answer 5

alkylating agents

Question 6

Which drug used to treat brain tumors is a non-enzymatically activated pro-drug yielding a DNA methylating agent?

Answer 6

Temozolomide

Question 7

Which drug is an alkylating agent and production of decomposition products that carbamylate proteins to inhibit DNA repair?

Answer 7

Carmustine (BCNU)

Question 8

What is the ROA of carmustine?

Answer 8

parenteral or wafers

Question 9

What is the ROA of lomustine (CCNU)?

Answer 9

oral

Question 10

What is the ROA of Temozolomide?

Answer 10

(PO, IV)

Question 11

What are the major toxicities associated with carmustine and lomustine?

Answer 11

• Thrombocytopenia, leucopenia, N/V
• Delayed pulmonary fibrosis or infiltrates
• Endocrine dysfunction with brain irradiation (hyperprolactinemia)

Question 12

What are the major DDIs associated with carmustine and lomustine?

Answer 12

cross resistance with other akylating agents

Question 13

Carmustine is used to treat what type of tumors?

Answer 13

Astrocytoma, brain metastases, malignant glioma, medulloblastoma

Question 14

Lomustine is used to treat what type of tumors?

Answer 14

malignant gliomas

Question 15

Temozolomide is used to treat which tumors?

Answer 15

GBM and astrocytoma (on label)

Malignant glioma or melanoma (off-label)

Question 16

Which of the drugs used to treat brain tumors is a teratogen?

Answer 16

temozolomide

Question 17

What are the major toxicities of temozolomide?

Answer 17

Myelosuppression (mild to moderate leucopenia and thrombocytopenia); N/V 1-3 hrs post therapy; Chills, fever, malaise, myalgias

Question 18

How do tumor cells become resistant to temozolomide?

Answer 18

Expression of WT- MGMT (wild type methylguanine methyltransferase) in tumor to excise toxic methyl lesions

Question 19

True or false: WT-MGMT is also expressed in blood cells and can prevent the myelosuppression?

Answer 19

FALSE

Question 20

When are carmustine wafers used?

Answer 20

packed into the area where a tumor (high grade glioma) has been excised to dissolve over time and eradicate any residual tumor that remains at the margins of the excision site

Question 21

What is it called when you use a catheter to deliver chemotherapeutic agent directly to tumor and surrounding tissue?

Answer 21

convection enhanced delivery

Question 22

What is “chemo-fog” an example of?

Answer 22

Chemotherapy Related Cognitive Impairment (CRCI)

Question 23

Who gets “chemo fog”?

Answer 23

long-term consequence of antitumor treatment with cytotoxic agents

Question 24

What are the symptoms of “chemo fog”?

Answer 24

impaired verbal and visual memory, attention, concentration, language, motor skills, multitasking and ability to organize information.

Question 25

Peripheral release of what is thought to mediate “chemo fog”?

Answer 25

TNF-alpha

Question 26

How does TNF-alpha cause “chemo fog”?

Answer 26

travels to the brain where it can damage the mitochondria and produce reactive nitrogen species via a glial-cell related mechanism