Biology of Disease

therapeutic use. The vinca alkaloids vincristine, vinblastine and vinorelbine
(Figure 17.27), all derived originally from the periwinkle plant Vinca rosea,
work in a similar manner to colchicine. Vinblastine is used in combination
with other drugs to treat testicular cancer, while vincristine is used in treating
leukemias. Vinorelbine is used in lung and breast cancer therapy. Paclitaxel,
otherwise known as taxol, and docetaxel or Taxotere (Figure 17.28) are derived
from the bark and needles of the Pacific yew tree, Taxus brevifolia (Figure 15.8
(B)). These drugs also target microtubules but in this case they prevent their de-
polymerization. Both drugs are used in the treatment of ovarian, breast and
lung cancer.

Topoisomerase inhibitors form a complex with DNA topoisomerase II
and inhibit DNA replication. Examples of this class of drugs include VP-
16, or etoposide, and VP-26, or teniposide, both of which are derivatives of
podophyllotoxin, which is derived from the mandrake plant, Madragora.
VP-16 is used in the treatment of small cell lung cancer (Section 17.8), testicular
cancer and lymphomas and VM-26 is used to treat childhood leukemia.

Drug Examples of clinical use

Chlorambucil chronic lymphocytic leukemia

slow growing nonHodgkin’s lymphomas;

Melphalan multiple myeloma

Cyclophosphamide breast cancer

lymphatic cancer

Ifosfamide testicular cancer

lung cancer

sarcoma

BCNU Hodgkin’s lymphoma

nonHodgkin’s lymphoma

malignant melanoma

multiple myeloma

CCNU brain tumors

Hodgkin’s and nonHodgkin’s lymphoma

Table 17.7Alkylating agents in cancer treatment

GENERAL TREATMENT OF CANCER

CZhhVg6]bZY!BVjgZZc9Vlhdc!8]g^hHb^i]:YLddY ).*

N

N

O

O

O H

H

Deoxyribose

Deoxyribose

Deoxyribose

P

F

N

N

O-

O H

H

P

F

N

N

O H

H

P

F

A) FdUMP

Thymidylate synthase

Thymidylate synthase

Thymidylate synthase

Methylene THF

Methylene THF

Figure 17.26(A) 5-Fluorouracil is converted

in vivo into the anticancer drug to

fluorodeoxyuridylate (FdUMP). In the presence

of methylene tetrahydrofolate (THF) this binds

irreversibly to thymidylate synthase, an essential

enzyme for DNA synthesis. (B) A molecular model

of thymidylate synthase with a bound FdUMP.

PDB file 1TSN.

B)

CH 3 OOC

CH 3 O

CH 2 CH 3

CH 2 CH 3

COOCH 3

HO

N

N

H

H

H

N

N

R HO

COOCH 3

Vinblastine R = CH 3

Vincristine R = CHO

Figure 17.27Structures of the vinca alkaloids, vinblastine and vincristine.