Yth. Peserta Diskusi ZOA-BIOTEK,

Berikut kami sampaikan bagian ke-2 dari makalah Prof. Ishikawa.

Moderator

Dedy

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Transport Mechanism-Based Drug Design 

With all this knowledge available, pharmaceutical companies are finding 
it important to design drug molecules that are neither substrates 
of drug efflux pumps nor affected by genetic polymorphisms. For example,
doxorubicin and daunorubicin, the first two clinically approved 
anthracyclines (Fig. 2 upper panel), as well as the more recently 
introduced epirubicin, are widely used in cancer chemotherapy, even 
though all three drugs are readily eliminated from human cancer cells 
by P-glycoprotein and have their activity hampered by multidrug resistance 
attributable to overexpression of P-glycoprotein. To circumvent this 
therapeutic problem, we devised a novel approach to more effective 
anthracyclines by considering the substrate recognition profile of 
P-glycoprotein 3,4). The result was a new drug called Annamycin.





Figure 2.

In arriving at the design and synthesis of Annamycin, our analysis 
of P-glycoprotein transport profile implicated the protonable 3'-
amino group in anthracyclines as an important structural element 
facilitating P-glycoprotein-mediated transport. In Annamycin, therefore,
the 3'-amino group was replaced with a hydroxyl group to reduce 
P-glycoprotein-mediated transport. In addition, other structural 
changes were made to increase lipophilicity and improve entrapment 
in liposomes, as well as to increase its ability to poison topoisomerase 
II. These specific changes were the removal of a methoxy group at 
C-4 and introduction of iodine at C-2'. The drug's entrapment in 
liposomes was intended to increase tumor targeting and reduce undesirable 
anthracycline-associated side effects such as cardiotoxicity. 

When Annamycin's cellular pharmacology was compared with that of 
doxorubicin in P388 (wild type-sensitive) and P388/DOX (multidrug-
resistant) cancer cell lines, Annamycin proved to be as active as 
doxorubicin against the sensitive line, but 50 to over 100 times 
more active against the resistant line 4). In general, Annamycin's 
cellular uptake in sensitive and resistant cells was higher than 
that of doxorubicin. In contrast to the rapid P-glycoprotein-mediated 
efflux of doxorubicin from resistant cells, Annamycin's efflux pattern 
was similar in both sensitive and resistant cells, thus suggesting 
that Annamycin was not a substrate of P-glycoprotein. Additionally.
it was shown that typical resistance reversing agents do not affect 
Annamycin uptake and retention. Interestingly, when the organ distribution 
and tumor uptake of Annamycin, liposomal Annamycin (L-ANNA), and 
doxorubicin were compared in C57BL/6 mice bearing advanced subcutaneous 
B 16 melanoma tumors, Annamycin levels were consistently higher than 
doxorubicin levels, except in the heart. The tumor levels of Annamycin 
and L-ANNA (as determined by the area under the curve, AUC) were 
2 and 5 times higher, respectively, than those of doxorubicin. 

Finally, the antitumor activities of Annamycin, L-ANNA (Annamycin 
in large unilamellar vesicles), S-ANNA (Annamycin in small unilamellar 
vesicles), and doxorubicin were examined in vivo in three tumor models 
(subcutaneous M-5076 reticulosarcoma Lewis lung carcinoma, and subcutaneous 
KB-3-1 and KB-VI human xenografts) (4). Fig. 2 (lower panel) depicts 
the survival of mice bearing liver metastases of M-5076 reticulosarcoma 
treated with free Annamycin (4 mg/kg), liposome-formulated Annamycin 
(4 mg/kg), and doxorubicin (10 mg/kg). In terms of survival, Annamycin 
was clearly superior to doxorubicin, and the liposomal formulation 
had a significantly positive effect on the survival rate of treated 
animals, with S-ANNA being consistently more effective than L-ANNA.
Both these and all of the results described above suggest that the 
incorporation of transport mechanism-based structural requirements 
into drug design strategy is critically important for the enhancement 
of anticancer drug efficacy and the development of new drugs (3,4).


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Figure 3.

Conclusion and Future Perspectives

In the last decade of the 20th century, the development of high throughput 
screening (HTS) and high speed analoging (HSA) technologies helped 
accelerate the drug discovery process. In the 21st century, emerging 
genomic technologies (i.e., bioinformatics, functional genomics, 
and pharmacogenomics) may shift the paradigm for drug discovery and 
development (Fig. 3). In the meantime, however, drug discovery and 
development will remain high-risk, high-stakes ventures with long 
and costly timelines. One practical way of lowering this inherent 
economic risk will be to integrate into the drug discovery process 
a transport mechanism-based design strategy whose aim is to create 
pharmacokinetically advantageous drugs. In the future, this approach 
will merge perfectly with medicine's goal of delivering "the right 
drug to the right patient at the right dose." Since passive transport 
(the fundamental mechanism of membrane transport of many lipophilic 
compounds) cannot by itself explain all cellular drug trafficking,
we should elucidate specific molecular mechanisms that underlie 
differences in the drug response of individual patients. One way 
to accomplish this goal will be to first understand the genetics 
of transporters and drug-metabolizing enzymes involved in absorption,
distribution, metabolism, and excretion (ADME) (Fig. 3). Obvious 
targets of this work will be ABC transporters, such as P-glycoprotein 
or MRPs. Other targets may be specific solute transporters, e.g.,
oligopeptide transporter (PepT1), monocarboxylic acid transporter 
(MCT1), organic anion transporter (Npt1), and cation transporter 
(OCTN1 and OCTN2) which are expressed, for example, in intestinal 
and renal epithelial cells, hepatocytes, and brain capillary endothelial 
cells and are each responsible for the transport of certain drugs.
In short, we believe that clarifying the transport mechanisms and 
quantitatively analyzing the pharmacokinetics of drug transporters 
will lead to more effective and rational molecular drug and more 
site-specific drug delivery in the post-genome era.

References 

1. Ishikawa T, et al. 2000. New nomenclature of human ABC transporter 
genes Xenobiotics, Metabolism and Disposition 15: 8-19. 
2. Hoffmeyer S. et al. 2000. Functional polymorphisms of the human 
multidrug-resistance gene: Multiple sequence variations and correlation 
of one allele with P-glycoprotein expression and activity in vivo.
Proceedins of National Academy of Science USA 97: 3473-4378. 
3. Priebe, W and Perez-Soler, R. 1993. Design and tumor targeting 
of anthracyclines able to overcome multidrug resistance: A double-
advantage approach. Pharmac. Ther. 60: 215-234, 1993. 
4. Consoli, U, et al. 1996. The novel anthracycline Annamycin is 
not affected by P-glycoprotein-related multidrug resistance: Comparison 
with idarubicin and doxorubicin in HL-60 leukemia cell lines. Blood.
88: 633-644. 






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