Search

The continued progress in our understanding of the biology of neoplasia and in the identification, cloning, and sequencing of genes critical to tumor cell function permits the exploitation of this information to develop specific agents that may directly modulate the function of these genes or their protein products. Antisense oligonucleotides are being investigated as a potential therapeutic modality that takes direct advantage of molecular sequencing. The antisense approach uses short oligonucleotides designed to hybridize to a target mRNA transcript through Watson-Crick base pairing. The formation of this oligonucleotide: RNA heteroduplex results in mRNA inactivation and consequent inhibition of synthesis of the protein product. A fundamental attraction of the antisense approach is that this method potentially may be applied to any gene product, in theory, for the treatment of malignant and non-malignant diseases. However, this simple and attractive model has proven to be much more complex in practice. A number of important challenges in the preclinical development of antisense oligonucleotides have been identified, including stability, sequence length, cellular uptake, target sequence selection, appropriate negative controls, oligonucleotide: protein interactions, and cost of manufacture. Although the biological activity of an oligonucleotide against its molecular target is theoretically sequence-dependent, the animal pharmacokinetics and toxicology of phosphorothioate analogues directed against vastly disparate gene products appear relatively non-sequence-specific. In oncology, a number of clinical trials have been initiated with antisense oligonucleotides directed against molecular targets including: p53; bcl-2; raf kinase; protein kinase C-alpha; c-myb. The experience gained from these early clinical trials will be applicable to the next generation of antisense agents in development. These may include molecules with novel backbones or other structural modifications, chimeric oligonucleotides, or peptide nucleic acids. Continued progress in this arena will require that many of the preclinical challenges confronting antisense development are satisfactory resolved.

Interest in retinoids as therapeutic agents has developed as a result of the observations of remission induction with all-trans retinoic acid (tRA) in patients with acute promyelocytic leukemia (APL), and of high objective response rates noted with the combination of cis-retinoic acid (cRA) with interferon-alpha in squamous cell carcinomas of skin and cervix. The therapeutic experience with RA in APL is discussed in this article from the perspectives of new information concerning retinoid biology, observations related to the development of the retinoid syndrome, complex pharmacology of this agent, and possible explanations for development of retinoid resistance. The current National Cancer Institute-supported drug development strategy for RA used alone or in combination with other differentiating agents, and the potential therapeutic uses in cancer for other retinoids are also discussed.

Interleukin-2 (IL-2) is a true biological response modifier. Unlike alpha-interferon, which acts directly, IL-2 mediates its antitumor effects through complex indirect effects on the immune system. IL-2 used alone shows documented antitumor activity, which is both dose and schedule related. Antitumor activity may be increased by the use of either IL-2 in combination with other cytokines or monoclonal antibodies or both types of agents in combination with activated effector cytotoxic lymphocytes. In humans, data suggest that IL-2s rapid initial clearance is due to movement into an extravascular compartment from which IL-2 returns more slowly to the plasma. Toxicity appears to be due entirely to IL-2, rather than to transfused lymphocytes. IL-2 administered by continuous infusion is superior to bolus administration. However, at total daily-dose equivalence continuous infusion of IL-2 is both more toxic and more biologically active than bolus administration, with respect to the height of post-IL-2 rebound lymphocytosis, the generation of activated circulating lymphocytes, and lymphokine-activated killer-cell precursors. The question remains unresolved as to whether the toxicity of IL-2 therapy is necessary for the attainment of optimal clinical results. From currently available data, it appears that a minority of patients treated with IL-2 show clinically significant responses, and only 5% to 10% achieve durable complete responses. Nevertheless, these reproducible responses have occurred in tumors refractory to more conventional treatment. The reasons for non-response are unclear, but many avenues of investigation suggest that IL-2 therapy may be made both more active and more tolerable through the use of alternative doses and schedules and the use of IL-2 in combination with defined antitumor effector lymphocytes, with concomitant or sequential administration of other cytokines, or together with monoclonal antibodies.