Drug Targeting Organ-Specific Strategies

204 8 Strategies for Specific Drug Targeting to Tumour Cells
transported.Also, there are certain membrane proteins which act as energy-dependent efflux
pumps for a number of commonly used chemotherapy drugs. Examples of these proteins are
P-glycoprotein (P-gp), first described by Juliano and Ling [15], as well as the multi-drug resistance
related protein (MRP), [16] and the lung resistance related protein (LRP) [17,18].
These proteins are either alone or in concert operative in the phenomenon known as multidrug
resistance (MDR).
Frequently used cytostatic agents which are involved in MDR are the anthracyclines (doxorubicin,
daunorubicin), vinca-alkaloids (vincristine, vinblastine), epipodohyllotoxins
(etoposide), and taxanes (paclitaxel). The most extensively studied mechanism is the overexpression
of P-gp, which is a 170-kDa transmembrane drug efflux pump encoded by the
MDR 1 gene in humans. Another mechanism is the over-expression of MRP, a 190-kDa drug
efflux pump, encoded by the MRP 1 gene.A third mechanism which is involved in MDR is the
heterotopic expression of LRP. This protein is extensively expressed in a variety of normal
tissues, especially in the bronchus, renal proximal tubulus, canalicular domain of the hepatocyte
[19], macrophages and adrenal cortex. In vitro studies also suggest that LRP has a role
in the compartmentalization and transport of chemotherapeutic drugs out of the tumour
cells.
Once a drug has entered the cell, detoxification mechanisms within the cytoplasm can potentially
inactivate cytotoxic drugs. These include the activity of glutathione and the glutathione-S-transferase
enzyme. At the nuclear level there is a wide variety of proteins available
to protect the cell against chemotherapy-induced damage. The topoisomerase enzymes
[20] are common targets for cytotoxic drugs. Topoisomerases are nuclear enzymes, which are
involved in DNA replication. Inhibitors of the topoisomerase-1 include agents based on the
camptothecin structure, topotecan and irinotecan. They stabilize the covalent complex between
DNA and topoisomerase-1 resulting in DNA breakdown and finally cell death. Inhibitors
of topoisomerase-2 include etoposide, teniposide and doxorubicin.
The malignant cell, similar to the normal cell, has a complex array of enzymes involved in
recognizing and repairing DNA damage. Increased levels of DNA repair enzymes have been
identified in models of resistance to cytotoxic drugs, in particular to methylating agents, with
elevations in O-methyltransferase, and in resistance to platinum-based drugs. So, in addition
to the tumour structure and physiological barriers, there is a variety of ways by which an individual
tumour cell can escape adequate targeting of drugs and/or their cytotoxic effects.
8.4.4 Pharmacokinetic Barriers
Before reaching the site of action (tumour cells), basic pharmacokinetic tolerance and whole
body distribution patterns of cytotoxic drugs play an important role in the final outcome of
drug treatment. As a result of unfavourable pharmacokinetics, patients are often unable to
tolerate effective doses due to unacceptable toxicity. This holds true especially for the more
conventional cytotoxic drugs. There is also a variability between patients in pharmacokinetic
tolerance of cytotoxic drugs, e.g. in parameters such as oral bio-availability of drugs, differences
in excretion rate (partially P-gp mediated), and altered metabolism through variations
in cytochrome P-450 iso-enzyme activities, particularly in the elderly.The vast majority of cytotoxic
drugs are metabolized via cytochrome P-450-dependent mechanisms, and many of