Chemistry Reference
In-Depth Information
13.3.1 Actinomycin D
The first microbial-derived agent in clinical use for cancer was actinomycin
D(
41
) (which was systematically named as D-actinomycin C
1
and generically
named dactinomycin) that was introduced in the early 1960s. Despite extensive
research into the preparation of analogs, no derivatives have progressed beyond
clinical trials (67). Its mechanism of action is inhibition of DNA-dependent RNA
synthesis, which in turn depends on the strong intercalation of actinomycin into
double-helical DNA (68, 69). It is used clinically in the treatment of trophoblastic
tumors in females, in metastatic carcinoma of the testis, and in Wilms's tumor
in children (67). In recent years there have been reports that actinomycin D may
also act on the signal transduction cascade(s) at the level of transcription fac-
tor(s), and it will be interesting to see whether these activities rejuvenate interest
in this class of molecules (70).
13.3.2 Bleomycins
Another important class is the family of glycopeptolide antibiotics known as
bleomycins (e.g., bleomycin A
2
and Blenoxane; Nippon Kayaku Co., Ltd., Tokyo,
Japan) (
42
); the bleomycins are structurally related to the phleomycins (71, 72).
Bleomycin was originally thought to act through DNA cleavage, because it
cleaves both DNA and RNA in an oxidative, sequence-selective, metal-dependent
fashion in the presence of oxygen. Recent studies, however, suggest that an
alternative mechanism of action may be inhibition of t-RNA from experiments
reported recently by the Hecht group (73). Bleomycins are used clinically in com-
bination therapy for the treatment of squamous cell carcinomas and malignant
lymphomas.
13.3.3 Mitomycins
The mitomycins (mitosanes) were discovered in the late 1950s, and mitomycin
C(
43
) was approved for clinical use in Japan in the 1960s and in the United
States in 1974. Its serious bone marrow toxicity has led to extensive synthetic
studies aimed at developing a less toxic analog but without significant success; it
remains the only clinically used member of this class. It alkylates DNA only after
undergoing a one-electron reduction. The current model postulates that mitomycin
C alkylates and cross-links DNA by three competing pathways (74). Clinically
it is used primarily in combination with other drugs for the treatment of gastric
and pancreatic carcinomas (75).
13.3.4 Calicheamicin
Calicheamicin (
44
) is a member of a large group of antitumor enediyne antibi-
otics. It was isolated from
Micromonospora echinospora
ssp.
calichensis
by
workers at Lederle Laboratories (Pearl River, NY, now Wyeth) (76, 77); the
