Topoisomerase ITargeting Agents

Camptothecin (CPT), a naturally occurring, relatively water-insoluble alkaloid extract from the bark and wood of the Chinese tree Camptothecan acuminata, is the prototype topoisomerase I-targeting agent. Its clinical development was halted early due to its toxicity and only upon the introduction of water-soluble forms was it reintroduced into clinical testing. The analogues have greater in vivo and in vitro activity and less severe and more predictable toxicity than camp-tothecin. All CPT analogues exhibit stereospecific-inhibition of topoisomerase I activity, with the naturally occurring S-isomer being up to 100 times more biologically active than the R-isomer. Nevertheless, they differ from classic enzyme inhibitors by not merely preventing the function of topoisom-erase alone; CPTs trap the enzyme in a covalent complex bound to DNA, leading to persistence of single-strand breaks and accumulation of stabilized cleavable complexes, which by themselves are not lethal because the strand breaks are reversible upon drug removal. Active DNA synthesis is a crucial component to CPT-induced cytotoxicity,101-103 making camptothecins relatively S-phase-specific agents, although non-S-phase-specific cytotoxicity has been described. According to the fork collision model,102 lethal damage to DNA occurs once a DNA replication fork encounters a cleavable complex, resulting in a cytotoxic double-stranded break in DNA. CPTs thus are more aptly termed topoisomerase I-targeting agents.

All CPTs undergo a rapid, reversible, pH-dependent, nonenzymatic hydrolysis of the lactone ring to generate the less-active open-ring hydroxy carboxylate in aqueous solutions. The latter species predominate at physiologic or alkaline pH. This finding is clinically relevant because the low pH in the bladder favors the active closed lactone ring species that can cause severe hemorrhagic cystitis. Among the CPT analogues, irinotecan is structurally unique in that it lacks direct activity per se. It is a prodrug that must undergo cleavage of its bulky dipiperidino side chain by a carboxylesterase-converting enzyme to produce the metabolite SN-38 for biologic activity.

Topotecan

Topotecan was the first water-soluble CPT analogue approved for clinical use. It has a relatively higher CNS penetration than most other CPTs, due in part to its low plasma protein binding. Schedule-dependent synergism with radiation (concurrent, preradiation, or within 30 minutes after radiation) in vitro has been observed. Renal excretion is the main route of drug elimination. Dosage adjustments are recommended for patients with moderate renal impairment (20-39mL/min). Hepatic metabolism by cytochrome P-450 enzymes is minimal. At the standard dose of 1.5 mg/m2/day for 5 consecutive days every 3 weeks, noncumulative and reversible neutropenia is the most common dose-limiting toxicity, with grade 4 neutropenia occurring in 81%, febrile neutropenia in 26%, grade 4 thrombocytopenia in 26%, and severe anemia (Hb less than 8g/dL) in 40%. Topotecan is approved for use in cisplatin-refractory ovarian cancer, recurrent small cell lung cancer failing frontline chemotherapy, and leukemias.

Irinotecan

As mentioned earlier, irinotecan (CPT-11) has little inherent antitumor activity in vitro. Its water-insoluble deesterifica-tion metabolite SN-38 is 1,000-fold more potent than the parent compound. SN-38 has a longer half-life and high binding affinity to plasma proteins, especially albumin. In contrast with topotecan and other CPT analogues, the lactone form of SN-38 is preferentially stabilized by albumin, hence the equilibrium is shifted toward the formation of the lactone in physiologic conditions. Although SN-38 formation occurs in the plasma and intestinal mucosa, conversion of irinote-can to SN-38 predominates in the liver. Moreover, differential activity of carboxylesterase in malignant tissues may contribute to tumor sensitivity to this agent.104 SN-38 undergoes glucuronidation in the liver mediated by UGT1A1 isoform of hepatic uridine diphosphate glucuronosyltrans-ferase. UGT1A1 expression is highly variable, and its activity varies 17- to 52-fold among individuals. UGT1A1 activity is deficient in patients with Gilbert's syndrome, which can occur in up to 15% of the population. Biliary excretion of SN-

38 and irinotecan is the major route of elimination. Entero-hepatic recirculation occurs as the glucuronidated SN-38 metabolite can be deconjugated by bacterial b-glucuronidases, thereby increasing exposure of the intestinal epithelium to SN-38. Ability to conjugate SN-38 and bilirubin, the endogenous substrate, is inversely related to myelosuppression, suggesting that agents that induce UGT activity, such as phenobarbital, may improve the therapeutic index of CPT-11. Certain polymorphisms of UGT1A1, such as in the promoter region with Gilbert's syndrome, have been correlated with decreased glucuronidating activity, resulting in increased risk for myelosuppression and diarrhea. Further elucidation of such polymorphisms and other pharmacogenetic variables will hopefully enable clinicians to better predict drug responses and toxicities. CPT-11 is approved for frontline therapy in metastatic colorectal carcinoma in combination with 5-FU and leucovorin.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment