Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 342

two main mechanisms of action. First, it inhibits DNA and RNA
synthesis by intercalating between base pairs of the DNA/RNA
strands, thus preventing the replication of rapidly growing cancer
cells. This mechanism is based on the chemistry and physics of
the doxorubicin molecule (its positively charged mannose amine,
which binds efficiently to negatively charged nucleic acid phosphate
diester groups, and the excellent fit of the drug anthroquinone planar
ring structure for intercalation into the double stranded DNA). All
together, these structural features lead to high affinity of the drug
to double stranded nucleic acids in a way that is not metabolism
dependent. Second, doxorubicin inhibits topoisomerase II enzyme,
preventing the relaxing of super-coiled DNA and thus blocking DNA
transcription and replication. Its third major biological eff ect is that
it forms iron-mediated free radicals that cause oxidative changes to
DNA, proteins, and cell membrane lipids. Especially sensitive are the
mitochondrial membranes due to their high level of the negatively
charged phospholipid cardiolipin, for which doxorubicin has high
affinity. This property was the basis of Rahman and coworkers' (1980,
1985, 1986a, 1986b) selection of cardiolipin as their formulation's
negatively charged lipid. This oxidative induced damaging eff ect is
now considered one of the main reasons for doxorubicin's toxicities
and side eff ects. The fact that heart muscle is enriched in mitochondria
explains in part the drug's cardiotoxicity. Routine treatment by
doxorubicin is given intravenously using a relatively high drug dose,
in the range of 10 to 50 mg/m 2 (rev. in Weiss, 1992; Skeel, 1999;
Minotti et al., 2004; Takimoto and Calvo, 2008; Kenyon, 2008).
Doxorubicin is considered one of the most eff ective anticancer
drugs ever developed, and therefore it became one of the main
“first line” anticancer drugs almost from its discovery. It is eff ective
against more types of cancer (including leukemias, lymphomas,
and breast, uterine, ovarian, and lung cancers) than any other class
of chemotherapy agents (Skeel, 1999; Weiss, 1992, Minotti et al.,
2004).
However, like most other chemotherapeutic drugs, doxorubicin
has toxicities and side eff ects attached to its use. Its most
dangerous toxicity is the cumulative dose-dependent cardiotoxicity
( irreversible congestive heart failure), which considerably limits
its usefulness (upper accumulative dose of 550 mg/m 2 ). Its other
side eff ects include severe myelosuppression, nausea and vomiting,
mucocutaneous eff ects [(stomatitis, alopecia, severe local tissue