Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 11, 2008


Contents

Anti-Cancer Drugs
Executive Editor: Elke Bergmann-Leitner


Editorial Pp.1048


Arginine Deprivation as a Targeted Therapy for Cancer Pp. 1049-1057
L. Feun, M. You, C.J. Wu, M.T. Kuo, M. Wangpaichitr, S. Spector and N. Savaraj
[Abstract]


Molecular Targeting Agents in Renal Cell Carcinoma: Present Strategies and Future Perspectives Pp. 1058-1077
S.K. Bjelogrlic, S. Radulovic and N. Babovic
[Abstract]


Design, Synthesis and Development of Novel Camptothecin Drugs Pp. 1078-1097
S.T. Liew and L-X. Yang
[Abstract]


Combinatorial Application of Nucleic Acid-Based Agents Targeting Protein Kinases for Cancer Treatment Pp. 1098-1112
B. Spänkuch and K. Strebhardt
[Abstract]


Chemosensitization of Cancer by Nitric Oxide Pp. 1113-1123
R. Sullivan and C.H. Graham
[Abstract]


Novel Approaches to Deliver Gemcitabine to Cancers Pp. 1124-1137
L.H. Reddy and P. Couvreur
[Abstract]


Locked Nucleic Acid Holds Promise in the Treatment of Cancer Pp. 1138-1142
M. Frieden and H. Ørum
[Abstract]


Methylenetetrahydrofolate Reductase (MTHFR): A Novel Target for Cancer Therapy Pp. 1143-1150
J. Stankova, A.K. Lawrance and R. Rozen
[Abstract]




Abstracts


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Editorial: Anti-Cancer Drugs

Intensive research to design chemotherapeutic therapies of cancer has been conducted for the last 70 years. Throughout the decades several groundbreaking observations have been made and countless compounds have been tested for their anti-neoplastic activities. Today we have arrived at a point where we understand in much greater detail the cell biology of tumor cells and are aiming at very specific cellular and nuclear targets. This will lead to much lower toxicities and potentially to wider clinical responses. Moreover, combination therapies combining chemotherapeutic and either radio- or immunotherapy might mark a new milestone in the fight against cancer.

The present issue of Anti-Cancer Drugs focuses on novel molecular approaches to cancer treatment and on studies aiding our understanding of the molecular events causing cancer or failure of treatment. As we learn more about the molecular changes in tumor cells and potential escape mechanisms such knowledge will assist in the design of efficacious cancer therapies for a large patient population.

S. Bjelogrlic et al. [1] summarize various approaches of molecular targeting to interfere or modulate protein activity or signal transduction in renal cell carcinoma cells. These efforts may lead to reversal of disease mechanism(s).

M. Frieden et al. [2] review the novel approach of locked nucleic acids (LNA) for targeting and inhibiting cancer-associated mRNAs. This novel third generation antisense treatment has been shown to be safe and effective and is currently under clinical evaluation.

Exploiting deficiencies in tumor cells at the metabolic level are novel anti-cancer strategies reviewed by L. Feun et al. [3]. The authors report on the advances in regards to targeting tumor cells that lack a key enzyme (argininosuccinate synthetase (ASS)). Depriving ASS-deficient cancer cells (e.g., melanoma, hepatocellular carcinoma, renal cancer) of arginine by treatment with an agent such as pegylated arginine deiminase (ADI-PEG) has been shown in Phase I and II clinical trials to exhibit anti-cancer effects.

J. Stankova et al. [4] summarize the critical role of folate and methionine metabolism in cancer cells and the targeting in anti-neoplastic therapies. The authors also review their work encompassing the metabolic target methylenetetrahydrofolate reductase and the in vitro and in vivo successes in reducing tumor growth. Similarly, B. Spaenkuch et al. [5] report on the attempt to silence cancer-related genes by antisense oligonucleotides or small interfering RNAs. Such approaches not only target genes that are crucial for the function of tumor cells, but also genes that confer protection by drug-resistance.

A different approach to modulating chemoresistance of tumor cells is reviewed by R. Sullivan et al. [6]. The authors assess the adjuvant effect of nitric oxide and nitric oxide mimetic agents for chemotherapy as such treatment frequently restores a chemosensitive phenotype. The mode of action is still under investigation and may be partly caused by increased blood supply, tumor oxygenation, antioxidant effects as well as the downregulation of many cellular enzymes and proteins involved in chemoresistance.

Lastly, new strategies revolving around two widely used chemotherapeutic drugs are described: L. Reddy et al. [7] describe new delivery strategies of gemcitabine, a nucleoside analog that will be incorporated by proliferating cells into newly synthesized DNA in place of cytidine and leads to the induction of apoptosis in these cells. T. Liew and L.-X. Yang [8] summarize the efforts of the pharmaceutical field for the design and development of DNA topoisomerase I inhibitors such as camptothecin and its derivatives.

I would like to thank all the authors for their efforts in reviewing their own research data and the encompassing body of literature in order to make this issue a comprehensive overview of current efforts to identify and target molecular pathways as well as to discover efficacious novel anti-cancer drugs.

References

[1] Bjelogrlic SK, Radulovic S, Babovic N. Molecular targeting agents in renal cell carcinoma: present strategies and future perspectives. Curr Pharm Des 2008; 14(11): 1049-1057.

[2] Frieden M, Henrik Ø. Locked Nucleic Acid holds promise in the treatment of cancer. Curr Pharm Des 2008; 14(11): 1058-1077.

[3] Feun L, You M, Wu CJ, Kuo MT, Wangpaichitr M, Spector S, Savaraj N. Arginine deprivation as a targeted therapy for cancer. Curr Pharm Des 2008; 14(11): 1078-1097.

[4] Stankova J, Lawrance AK, and Rozen R. Methylenetetrahydrofolate reductase (MTHFR): a novel target for cancer therapy. Curr Pharm Des 2008; 14(11): 1098-1112.

[5] Spänkuch B, Strebhardt K. Combinatorial application of nucleic acid-based agents targeting protein kinases for cancer treatment. Curr Pharm Des 2008; 14(11): 1113-1123.

[6] Sullivan R, Graham CH. Chemosensitization of cancer by nitric oxide. Curr Pharm Des 2008; 14(11): 1124-1137.

[7] Reddy LH, Couvreur P. Novel approaches to deliver gemcitabine to cancers. Curr Pharm Des 2008; 14(11): 1138-1142.

[8] Liew ST, Yang L-X. Design, Synthesis and development of novel camptothecin drugs. Curr Pharm Des 2008; 14(11): 1143-1151.


Elke Bergmann-Leitner
Department of Medicine
Uniformed Services University of the Health Sciences
Bethesda, MD 20814
USA


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Arginine Deprivation as a Targeted Therapy for Cancer
L. Feun, M. You, C.J. Wu, M.T. Kuo, M. Wangpaichitr, S. Spector and N. Savaraj

Certain cancers may be auxotrophic for a particular amino acid, and amino acid deprivation is one method to treat these tumors. Arginine deprivation is a novel approach to target tumors which lack argininosuccinate synthetase (ASS) expression. ASS is a key enzyme which converts citrulline to arginine. Tumors which usually do not express ASS include melanoma, hepatocellular carcinoma, some mesotheliomas and some renal cell cancers. Arginine can be degraded by several enzymes including arginine deiminase (ADI). Although ADI is a microbial enzyme from mycoplasma, it has high affinity to arginine and catalyzes arginine to citrulline and ammonia. Citrulline can be recycled back to arginine in normal cells which express ASS, whereas ASS(-) tumor cells cannot. A pegylated form of ADI (ADI-PEG20) has been formulated and has shown in vitro and in vivo activity against melanoma and hepatocellular carcinoma. ADI-PEG20 induces apoptosis in melanoma cell lines. However, arginine deprivation can also induce ASS expression in certain melanoma cell lines which can lead to in vitro drug resistance. Phase I and II clinical trials with ADI-PEG20 have been conducted in patients with melanoma and hepatocellular carcinoma, and antitumor activity has been demonstrated in both cancers. This article reviews our laboratory and clinical experience as well as that from others with ADI-PEG20 as an antineoplastic agent. Future direction in utilizing this agent is also discussed.


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Molecular Targeting Agents in Renal Cell Carcinoma: Present Strategies and Future Perspectives
S.K. Bjelogrlic, S. Radulovic and N. Babovic

Treatment options for metastatic renal cell carcinoma (RCC) have been limited due to its resistance to chemotherapy and radiotherapy. Benefits from immunotherapeutic agents provide only a small subset of patients. During the past decade major advances have been made toward understanding the molecular basis of RCC development. Such acquired knowledge has offered unique opportunities for the development of molecular targeting agents. These agents are predominately small molecules or monoclonal antibodies that exert their action through modulation of protein activity or inhibition of amplified signals directly implicated in disease mechanism. To date, some of newly molecular targeted agents have entered advanced phases of clinical development, received marketing authorization by regulatory agencies and have opened a possibility of multiple treatment options. This article overviews current knowledge in RCC molecular pathology with recent clinical data, and discuss present strategies for future development of targeted therapies.


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Design, Synthesis and Development of Novel Camptothecin Drugs
S.T. Liew and L-X. Yang

For almost 5 decades later since it was first discovered in 1958, efforts continue to be made in the medicinal chemistry of camptothecin (CPT) and its derivatives. Thousands of CPT analogues have been prepared. However, many of the earlier CPT derivatives were either too toxic for clinical use or had very poor pharmacokinetics. Efforts in the last 2 decades were most successful and two derivatives, Irinotecan and topotecan, have been clinically approved by the FDA. This review mainly summarizes the design and synthesis of camptothecin drugs in various stages of preclinical or clinical developments.


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Combinatorial Application of Nucleic Acid-Based Agents Targeting Protein Kinases for Cancer Treatment
B. Spänkuch and K. Strebhardt

The progress made in cancer biology, genetics and biotechnology has led to a major transition in cancer drug design and development, from an emphasis on non-specific, cytotoxic agents to specific, molecular-targeted smart cancer drugs. Many of these targeted agents have shown to have improved selectivity for cancer versus normal cells and are associated with better anti-tumor efficacy and lower toxicity. The new generation of anti-cancer drugs requires low concentrations and minimizes unwanted side effects. Their use leads to enhanced anti-cancer effects and to a reduction of chemotherapy resistance. Still, resistance to common chemotherapeutic agents is a major obstacle in cancer treatment. Silencing of cancer-relevant genes is a challenging strategy to reduce resistance and to sensitize can-cer cells towards anti-neoplastic agents. Resistance can be an intrinsic problem of the tumor or can be acquired during the life time of the tumor. A fascinating species of anti-cancer drugs include antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs) which are able to specifically down-regulate the expression of the target genes. The combination of nucleic acid-based agents with anti-neoplastic drugs can induce synergistic induction of cell cycle arrest, apoptosis and reduced cell proliferation in vitro or tumor growth in vivo. These two strategies (ASOs and siRNAs) will help to improve current therapeutic regimens. In addition, the combination of targeted drugs with common chemotherapeutic agents might be able to make resistant cells again sensitive towards a chemotherapeutic agent.


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Chemosensitization of Cancer by Nitric Oxide
R. Sullivan and C.H. Graham

Recent evidence from experimental and clinical studies links the development of intratumoral hypoxia and oxidative stress with malignant progression. Cellular adaptation induced by these environmental stresses is also associated with the emergence of drug resistant populations. This adaptation is most likely a multifactorial process involving coordination of various stress-induced signaling pathways, including those regulated by hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB) together with their down-stream targets linked to resistance mechanisms. Experimental data suggest that treatment of human cancer cells with nitric oxide (NO) and NO mimetic agents can effectively restore the sensitivity of resistant populations to the cytotoxic effects of chemotherapeutics both in vitro and in vivo. Furthermore, preliminary results from Phase II clinical trials evaluating NO as an adjuvant to chemotherapy are promising. The present review highlights the significance of intratumoral hypoxia and oxidative stress in the emergence of multidrug resistance, and summarizes the latest data demonstrating the chemosensitizing ability of NO. To date, the specific mechanisms through which NO restores sensitivity to anticancer agents are not clearly understood. However, the data suggest that chemosensitization is likely to involve NO-mediated activities associated with both prevention and inhibition of cellular drug resistance mechanisms. Potential mechanisms contributing to the chemosensitizing activity of NO include vascular changes that promote increased blood delivery and tumor oxygenation, antioxidant effects and down-regulation of the glutathione detoxification/redox buffering system, inhibition of key transcription factors such as HIF-1 and NF-κB, as well as inhibition of drug efflux transporters and DNA repair enzymes.


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Novel Approaches to Deliver Gemcitabine to Cancers
L.H. Reddy and P. Couvreur

The objective of this review is to discuss the strategies adopted to improve the delivery of gemcitabine to tumors. Concomitant research in this area has implemented a wide variety of approaches such as, aerosolized formulations, prodrug conjugates, liposomes, nanoparticles and beads. Some of these strategies were also aimed at overcoming the rapid metabolization and drug resistance associated with gemcitabine. Aerosolized formulations were employed to treat the local tumors, while other approaches were aimed at the systemic therapy of cancers. The liposomal formulations considerably increased the half-life and the area under the curve (AUC) of gemcitabine, and simultaneously caused a marked improvement in the anticancer activity against experimental solid tumors developed orthotopically or at subcutaneous site. Alternatively, the prodrug conjugates of gemcitabine displayed considerable activity in vivo against various tumors. Especially, in the case of leukemia in which gemcitabine was demonstrated to be inactive, the lipidic conjugates displayed marked efficiency following systemic and oral administration. These conjugates induced greater apoptosis and also caused resistance reversal in the resistant leukemia types. Altogether, the delivery strategies adopted for gemcitabine led to a considerable improvement in the treatment of cancers at the preclinical stage, and some of them are potential candidates for clinical trials.


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Locked Nucleic Acid Holds Promise in the Treatment of Cancer
M. Frieden and H. Ørum

Providing novel treatments to help cancer patients live longer and have better lives remains one of the biggest challenges of the pharmaceutical industry. Today much is known about the molecular and genetic causes of cancers thus facilitating the development of novel targeted cancer drugs with improved risk-benefit ratios compared to contemporary broadly-acting, cytotoxic cancer drugs. Antisense therapy, e.g. the use of single stranded oligonucleotides as therapeutic modalities, provides the means to develop such targeted drugs, and in recent years this concept has enjoyed a major renaissance. Locked Nucleic Acid (LNA) is a novel, third generation RNA analogue that displays most if not all of the characteristics required to make potent and safe antisense drugs. Here we review the key properties of LNA oligonucleotides in the context of their use as safe and effective antisense drugs and provide a status on their therapeutic development in the field of cancer.


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Methylenetetrahydrofolate Reductase (MTHFR): A Novel Target for Cancer Therapy
J. Stankova, A.K. Lawrance and R. Rozen

Tumor cells have an enhanced requirement for glucose, amino acids and DNA precursors. Since folates are required for the synthesis of thymidine and purines, the metabolism of folate has been exploited as an anti-cancer target for over 6 decades, with emphasis on the inhibition of DNA synthesis. However, folate is also used to generate methionine, which is essential for proliferation by virtue of its role in protein synthesis, polyamine synthesis and transmethylation reactions. Tumor-derived cell lines and human tumor xenografts have been shown to be methionine dependent i.e., they are unable to survive without methionine and are unable to efficiently utilize homocysteine, the immediate metabolic precursor of methionine. Since non-transformed cells are methionine-independent, the targeting of methionine metabolism presents an opportunity to selectively disrupt the unique metabolic networks in cancer cells.

This chapter provides an overview of the critical role of folate and methionine metabolism in tumor cells and summarizes the current anti-folate and anti-methionine strategies to inhibit growth of transformed lines and tumors. We also present our work on the development of a novel anti-cancer target, methylenetetrahydrofolate reductase (MTHFR), a key enzyme of both folate and methionine metabolism. Our data demonstrate that antisense-mediated inhibition of MTHFR is associated with increased cytotoxicity in vitro and with decreased growth of tumors in vivo. These findings warrant further investigation of this enzyme and the methionine biosynthetic pathway in exploring new strategies for cancer chemotherapy.