Researchers are studying various cellular processes in normal and diseased states to find new anticancer drug targets. They develop a medication that inhibits an intracellular enzyme that converts adenosine to inosine. With drug use, accumulation of enzyme substrates in the neoplastic cells leads to DNA strand breaks and subsequent apoptosis. Which of the following malignancies is likely to be most responsive to this medication?
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Adenosine deaminase (ADA) is a highly conserved enzyme that plays a crucial role in purine metabolism. ADA removes the amino group from adenosine/deoxyadenosine and replaces it with a keto group, leading to the formation of inosine/deoxyinosine. These compounds are subsequently converted into nontoxic waste products (hypoxanthine and uric acid) and are excreted.
ADA inhibition results in the metabolism of deoxyadenosine through an alternate pathway, whereby it is phosphorylated into the toxic metabolite deoxyadenosine triphosphate. Elevated intracellular levels of deoxyadenosine triphosphate activate the caspase system and also inhibit ribonucleotide reductase from converting ribonucleotides to deoxyribonucleotides, which depletes cells of DNA precursors. This ultimately results in the inhibition of DNA synthesis/repair and subsequent apoptosis.
Although all human cells contain ADA, developing lymphocytes are among the most mitotically active cells; the inhibition/absence of ADA is highly lymphocytotoxic. Therefore, ADA inhibitors (eg, cladribine) can be used to treat lymphocyte-derived cancers such as hairy cell leukemia. Similarly, children born with mutations to both ADA genes have dramatic B- and T-lymphocyte impairment, leading to the most severe form of severe combined immunodeficiency.
(Choices B, C, and E) Malignant melanoma is an aggressive melanocyte tumor that metastasizes early and is associated with high mortality rates when diagnosed at an advanced stage. Ovarian teratoma is an ovarian germ cell tumor that can be benign (mature) or malignant (immature). Soft tissue sarcoma is a mesenchymal tumor that tends to grow slowly over time. These tumors are not derived from lymphocyte cells and are not generally responsive to ADA inhibition.
(Choice D) Small cell lung cancer is a fast-growing neuroendocrine tumor that is most common in smokers. Fast-growing tumors are more likely to express elevated levels of ADA; however, ADA inhibition is primarily cytotoxic to lymphocyte-derived tumors and has not been shown to be of significant benefit to other cancer types.
Educational objective:
Adenosine deaminase (ADA) inhibition/absence is highly lymphocytotoxic. Medications that block ADA are used to treat lymphocyte-derived cancers. Inherited gene mutations in ADA lead to the autosomal recessive disease of severe combined immunodeficiency.