CLINICAL STUDIES OF CAMPTOTHECIN AND DERIVATIVES

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This chapter discusses the clinically important aspects of the camptothecins (CPT) alkaloids with an emphasis on their mechanisms of action and resistance, their pharmacokinetic and pharmacodynamic behavior, and their routes of administration. The CPTs are a class of effective anticancer drugs derived from plant alkaloids that exert their action against DNA topoisomerase I and have been developed in recent years. This specific mechanism of action and the activity against a broad spectrum of malignancies perpetuated a stimulus for research and clinical development of several CPT derivatives with improved physicochemical and pharmacological properties. At present, two analogs, viz. irinotecan and topotecan are registered for clinical use for the treatment of first- or second-line therapy in advanced colorectal cancer and second-line therapy in cisplatin-refractory ovarian cancer, respectively. Furthermore, in Japan irinotecan is also registered for the treatment of non-small cell lung cancer. Other members of this promising class of cytotoxic agents, including 9-Aminocamptothecin, 9-nitrocamptothecin, exatecan, diflomotecan, and lurtotecan are in progress of clinical development to specify their definite place in the spectrum of anticancer treatment.

Introduction

About a half century ago, thousands of natural products were chemically screened in a program initiated by the National Cancer Institute to search for steroidal sapogenins which would be cortisone precursors. This program led to the discovery of the plant alkaloids, the camptothecins (CPTs) – isolated from the stem wood of the Chinese tree Xi Shu or Camptotheca acuminata (Decaisne, Nyssaceae) ([1], [2], [3], [4], [5]). Initial in vitro and in vivo studies using the chloroform extract of the aqueous ethanolic residue of C. acuminata suggested widespread antitumor activity ([2], [3]). Camptothecins are related to the monoterpenoid indole alkaloids, and the parent alkaloid was shown to be a high-melting substance [molecular weight (MW) 348.111] comprising a unique and highly unsaturated pentacyclic-ring structure ([1], [3]). The structures of CPT and selected analogs are shown in Fig. 1.

The six-membered quinoline B-ring and the five-membered C-ring are formed by a ring expansion and contraction sequence of reactions. The E-ring presents a α-hydroxylactone system which can undergo a pH-dependent reversible hydrolysis. Camptothecin forms the sodium salt of a hydroxy acid after adding alkali and is relactonized on acidification. Both the E-ring and the D-ring, which has a conjugated pyridone moiety, are essential structural features for the antitumor activity of CPT (3).

Triggered by the preclinical antitumor activity, early Phase I clinical trials were performed in the early 1970s using CPT as a water-soluble sodium salt formulation, because of its ease of use as an intravenous (i.v.) formulation (6). Although in the first Phase I study five, short-lasting partial remissions were reported in 18 patients with primarily gastrointestinal cancers, these results could not be confirmed in subsequent Phase I and II studies in the USA ([7], [8], [9]). In contrast, a large program in the People's Republic of China involving up to 1000 patients treated with the sodium salt formulation of CPT reported favorable results, but for a variety of reasons these had to be interpreted with caution (3). However, unpredictable severe adverse events, i.e., life-threatening diarrhea, considerable hemorrhagic cystitis, and myelosuppression, likely related to the poor aqueous solubility of the parent compound, led to the suspension of the further development of this antineoplastic agent during the next two decades. The recognition that the nuclear enzyme DNA topoisomerase I was the prime target in the mechanism of action of the CPTs, and the possibility to develop numerous semisynthetic CPT analogs with improved aqueous solubility, and, in consequence, a more predictable toxicity profile, resulted in renewed interest in these cytotoxic agents.

Currently, two CPT derivatives, irinotecan and topotecan, are registered for use in oncologic practice. Irinotecan is registered for use in metastatic colorectal cancer. Topotecan is approved for the treatment of patients with cisplatin-refractory ovarian cancer and for small-cell lung cancer (SCLC) after the failure of first-line chemotherapy. During the last 10 years, knowledge of the pharmacokinetic and pharmacodynamic properties of the semisynthetic CPT analogs has significantly increased. The next challenge in their development will be to maximize efficacy and to minimize side effects in the treatment by biomodulation of the pharmacokinetic and pharmacodynamic properties. For instance, the pharmacological profile of irinotecan is extremely complex and the various processes involved in drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize irinotecan administration schedules based on patient profiles in enzyme and protein expression or by co-administration of specific agents modulating side effects are under investigation (10). Once the results of pharmacogenetics can be more crystallized, this may ultimately lead to more selective or “tailor-made” dose scheduling for patients to adjust the “fine-tuning” administration of these agents.

In this review, we will focus on the clinically important aspects of the CPT alkaloids with an emphasis on their mechanisms of action and resistance, their pharmacokinetic and pharmacodynamic behavior, and their routes of administration.

Section snippets

Mechanisms of Action

The cytotoxic CPTs belong to the class of topoisomerase I inhibitors. DNA topoisomerases are essential enzymes found in all nucleated cells. These enzymes are involved in the regulation of DNA topology and are necessary for the preservation of the integrity of the genetic material during DNA metabolism, e.g., RNA transcription, DNA replication, recombination, chromatin remodeling, chromatin condensation, and repair during cell division ([11], [12]). Based on their different reaction mechanism

Mutagenicity and Resistance Mechanisms

Owing to their mechanism of action, topoisomerase I inhibitors are a double-edged sword, because besides their cytotoxic properties, these agents are potential mutagens, although their mutagenicity and oncogenicity still remain to be elucidated ([31], [32], [33]). This is stressed by the fact that mutations may lead to drug resistance, limiting further treatment, or to the development of secondary malignancies. If mutations arise in germ cells, this could eventually be transmitted to subsequent

CLINICAL PHARMACOLOGY

Irinotecan (CPT-11; 7-ethyl-10-{4-[1-piperidino]-1-piperidino}-carbonyloxycamptothecin) is a semisynthetic, water-soluble prodrug that requires hydrolysis or de-esterification by carboxylesterases to form its active-metabolite SN-38 (7-ethyl-10-hydroxycamptothecin), which is 100–1000-fold more cytotoxic in vitro than the parent compound (65). Irinotecan contains a dibasic, bispiperidine substituent, linked through a carbonyl group to the hydroxyl at C-10, crucial for water solubility.

Irinotecan

CLINICAL PHARMACOLOGY

Topotecan (TPT; 9-dimethylaminomethyl-10-hydroxycamptothecin) is a semisynthetic, water-soluble CPT derivative, synthesized by modification of 10-hydroxycamptothecin (155). It undergoes CYP3A-catalyzed metabolism to N-desmethyl topotecan. N-Desmethyl topotecan is a less-active metabolite of which only low plasma levels were found, suggesting minimal CYP3A-related conversion. Nonetheless, clinical trials have shown significantly altered clearance of topotecan in patients on CYP3A-inducing

Considerations of Route of Administration

As mentioned earlier, cytotoxicity of topoisomerase I inhibitors increases with the duration of exposure. In vitro studies showed that short-term exposures to high concentrations are less effective than long-term exposure to low concentrations ([29], [30]). Low-dose, prolonged exposure in vivo studies in animal models also resulted in less toxicity ([242], [243], [244], [245], [246]). On the other hand, in vitro and animal models have shown to be poor predictors of clinical efficacy and

9-SUBSTITUTED CAMPTOTHECINS

9-Aminocamptothecin (9-AC) is a semisynthetic CPT derivative which showed outstanding preclinical activity against a wide spectrum of tumor types, including those of breast, colon, lung, prostate, and melanoma (255). In clinical trials, the drug has been very extensively studied using two different formulations based on the use of dimethylacetamide/polyethylene glycol 400 or a colloidal dispersion preparation, which enhances solubility and stability. Clinical Phase I investigations have been

Conclusions

The CPTs are a class of effective anticancer drugs derived from plant alkaloids that exert their action against DNA topoisomerase I and have been developed in recent years. This specific mechanism of action and the activity against a broad spectrum of malignancies perpetuated a stimulus for research and clinical development of several CPT derivatives with improved physicochemical and pharmacological properties. At present, two analogs, viz. irinotecan and topotecan are registered for clinical

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