Elsevier

The Lancet Oncology

Volume 10, Issue 1, January 2009, Pages 61-71
The Lancet Oncology

Review
Anti-HIV drugs for cancer therapeutics: back to the future?

https://doi.org/10.1016/S1470-2045(08)70334-6Get rights and content

Summary

The use of anti-HIV drugs as cancer treatments is not new. Azidothymidine was studied as an antineoplastic in the 1990s, but despite promising in vitro data, clinical trials showed little antitumour activity. HIV protease inhibitors were developed in the early 1990s, and their subsequent incorporation into highly active antiretroviral therapy (HAART) has profoundly changed the natural history of HIV infection. The potential antitumour properties of these drugs have been investigated because of their success in treating HIV-related Kaposi's sarcoma. HAART's effects on Kaposi's sarcoma did not always correlate with immune reconstitution, and activity against other solid and haematological malignancies has been established. Inhibition of tumour-cell invasion and angiogenesis were properties first ascribed to inhibition of HIV protease; however, they have pleiotropic antitumour effects, including inhibition of inflammatory cytokine production, proteasome activity, cell proliferation and survival, and induction of apoptosis. HIV protease inhibitors are thus a new class of anticancer drugs with multiple effects, and other anti-HIV drugs might hold similar promise.

Introduction

Sir James W Black—the pharmacologist and 1988 Nobel laureate in medicine—famously said the “most fruitful basis of the discovery of a new drug is to start with an old drug” (figure 1). The development of new treatments for cancer is both time-consuming and enormously costly. An analysis of 68 approved drugs estimated that it takes an average of 15 years and US$802 million (in US dollars at prices and exchange rates in the year 2000) to successfully develop a new drug.1 If postmarketing safety costs are included, total costs rise to nearly $900 million (figure 2).2 Consequently, the repositioning of old drugs for alternative purposes, such as cancer treatment, is timely. Several successful examples of repositioned drugs in the treatment of cancer exist. Retinoic acid, originally developed for acne is approved for the treatment of acute promyelocytic leukaemia. Arsenic trioxide, known as the oldest drug in the world, is also approved for the treatment of the same disorder. Perhaps the most successfully repositioned drug is thalidomide: originally developed as a sedative for pregnant women (with disastrous birth-defect results), it is now approved for therapy of multiple myeloma. These successes prove the feasibility of developing existing, approved drugs for cancer therapeutics. Anti-HIV drugs target multiple pathways of the HIV life cycle, and provide a large source of potential anticancer drugs.

Section snippets

Azidothymidine

Jerome Horwitz of Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine synthesised zidovudine (azidothymidine), the first antiviral drug used to treat HIV, in 1964. The compound was first synthesised as a treatment for cancer, but had little anticancer activity and unacceptable toxicity. No further research with zidovudine was pursued until 1984, when Marty St Clair discovered that the drug inhibited growth of HIV in vitro.3 Within months, Samuel Broder and

Non-nucleoside inhibitors of reverse transcriptase

Undifferentiated cells and embryos express large amounts of endogenous reverse transcriptase of retroposon or retroviral origin, which enables them to retrotranspose autonomously.27 Nevirapine and efavirenz reduced proliferation, induced morphological differentiation, and reprogrammed gene expression in transformed melanoma and prostate carcinoma cells without inducing apoptosis. Further, efavirenz inhibited the growth of xenografted melanoma, prostate, colon, and small-cell lung carcinoma

HIV-protease inhibitors

Development of HIV-protease inhibitors in the early 1990s followed the characterisation of the crystal structure of HIV protease in 1989.30 Inhibitors of HIV protease are peptidomimetics that generally contain a synthetic analogue of the peptide bond between phenylalanine and proline at postions 167 and 168 of the gag-pol polyprotein, which is the target of the HIV aspartyl protease (figure 3).32, 33 The first inhibitor of HIV protease developed that received FDA approval was saquinavir (figure

Chemokine-receptor antagonists

Chemokines are secreted factors first described as regulators of leucocyte trafficking during inflammation.80 Chemokine CXCL12 binds its cognate cellular receptor CXCR4. Chemokine receptors CXCR4 and CCR7 are present in several types of cancer and involved in progression and metastasis.81 CXCR4 is an important co-receptor for entry of T-tropic (X4) HIV in addition to CD4 for membrane fusion and entry into the cell, and CXCR4 antagonists have been developed for HIV therapy.82 HIV drugs that

Conclusion

Development of new drugs for cancer therapy is a lengthy and costly endeavour. In addition to the obvious financial benefits, the repositioning of an approved drug for cancer therapeutics has other advantages, such as implicit knowledge of its toxicity profile, drug metabolism, pharmacokinetics, and drug interactions. Although nucleoside analogues, such as zidvudine, cidofovir, and ganciclovir, have very limited roles in non-HIV-related cancer treatment, non-nucleoside reverse transcriptase

Search strategy and selection criteria

Data for this review were identified by searches of PubMed, Medline, and references from relevant articles with the search terms “anti-HIV agents” and “cancer”. Additional references were selected from relevant articles. Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English between January, 1992, and June, 2008, were included.

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