Biomedical Engineering Reference
In-Depth Information
Most anti-tumor drugs in clinical use act on metabolic pathways
related to cell growth and high mitotic activity. In addition, many
anti-cancer agents are low-molecular-weight compounds that
readily gain access to all cells. These highly non-specific eff ects
cause serious damage to healthy tissues while treating the tumor,
thus leading to dose-limiting side eff ects and impaired quality of
life. Chemotherapeutic treatment is often restricted by dose limiting
systemic toxicity, or by the appearance of drug resistance. Moreover,
the formulation of poorly soluble drugs may cause additional side
eff ects. Therefore, there is much to gain by conjugating such drugs
to polymeric carrier for anti-neoplastic therapy. The most commonly
used polymer conjugated drugs are camptothecin, paclitaxel,
doxorubicin, and platinum. Examples of polymer-drug conjugates in
the pipeline are listed in Table 4.4.
The first polymer-drug conjugate to enter clinical trials was PK1,
a HPMA copolymer-doxorubicin conjugate [107]. Doxorubicin (DOX)
is the most commonly used anthracycline anti-tumor antibiotics.
It has a wide range of anti-tumor activity, and is eff ective in the
treatment of carcinomas of the breast, lung, thyroid, ovary, and soft
tissue sarcomas. However, anthracycline therapy is associated with
significant general organ toxicities, especially myelosuppression,
mucositis, and cardiac toxicity. PK2, which is the relative conjugate
of PK1, possesses an additional targeting residue — a galactosamine
group that is the ligand for asialoglyoprotein. PK2 was designed
with the aim of improving treatment of primary hepatocellular
carcinoma and metastatic liver disease. In early phase I/II clinical
trials, both PK1 and PK2 displayed reduced twofold to fivefold
anthracycline toxicity, and the dose-limiting toxicities were typical
of the anthracyclines, which included febrile neutropenia and
mucositis. Despite high cumulative doses of DOX, no cardiotoxicity
was observed. Furthermore, no signs of immunogenicity or polymer
related toxicity were observed [107, 108]. Phase II study of PK1
for the treatment of breast and colorectal carcinomas and non-
small cell lung cancer (NSCLC) confirmed these results. No activity
against colorectal cancer, and activity restricted to anthracycline-
naive patients in breast cancer were observed. However, the activity
of PK1 against NSCLC was encouraging with 11.5% response rate,
even though DOX is known to have minor eff ect in NSCLC [109]. DOX
was also conjugated to dextran and tested clinically (phase I) [23].
However, this study was not continued, probably due to the reduced
biodegradability of the conjugated dextran [110].
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