Crystalline Camptothecin-20(S)-O-Propionate Hydrate: a Novel Anticancer Agent with Strong Activity Against 19 Human Tumor Xenografts
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Published OnlineFirst May 19, 2009; DOI: 10.1158/0008-5472.CAN-08-4452 Research Article Crystalline Camptothecin-20(S)-O-Propionate Hydrate: A Novel Anticancer Agent with Strong Activity against 19 Human Tumor Xenografts Zhisong Cao, Anthony Kozielski, Xing Liu, Yang Wang, Dana Vardeman, and Beppino Giovanella CHRISTUS Stehlin Foundation for Cancer Research, Houston, Texas Abstract catabolism of 5-FU, dihydropyrimidine dehydrogenase (DPD) To find a more effective and less toxic chemotherapeutic agent, serves as the initial and rate-limiting enzyme. A DPD deficiency is increasingly being recognized as an important pharmacogenetic we have successfully prepared crystalline camptothecin-20(S)- condition involved in the etiology of severe 5-FU–associated O-propionate hydrate (CZ48) by reacting camptothecin with toxicity. It has been reported that cancer patients who were propionic anhydride using concentrated sulfuric acid as genetically heterozygous or homozygous for a mutant allele of the catalyst. The biological effectiveness of this new anticancer gene encoding DPD suffered from more severe toxicity and even agent was evaluated by using xenografts of human cancers death following the administration of 5-FU (1, 2). Platinum agents, in nude mice as the testing models. The extensive treatment also commonly used in chemotherapy, exhibit other toxicities; a of 21 human tumors with various dose levels of CZ48 has substantial body of literature documents the side effects of shown that this agent is highly effective against many platinum compounds. Cisplatin, for instance, has multiple different human tumors tested with a striking lack of toxicities, including nephrotoxicity, neurotoxicity, ototoxicity, toxicity. Of the 21 human tumor lines tested, 9 regressed, 5 nausea, and vomiting (3). The nephrotoxicity of cisplatin almost were <10% of the control, 3 were <20%, and 2 were <40%. led to its abandonment until Cvitkovi and colleagues (4, 5) Two tumors did not respond. The total response rate was introduced aggressive hydration, which prevented the develop- 90% (19 of 21). No toxicity was observed in mice. The ment of acute renal failure. Thus, the toxicity of cisplatin actually effective doses required to achieve the positive response became a driving force in the history of chemotherapy in the varied from 100 to 1,000 mg/kg/d depending on the tumors. search both for less toxic analogues and for more effective The maximum tolerated dose was not reached because of treatment of the side effects of the drug. For other platinum the nontoxic nature of the drug in mice. Thus, this agents such as carboplatin, myelosuppression, which is not usually compound has a much wider therapeutic index compared severe with cisplatin, presents as the dose-limiting toxicity (6), and with that of the existing anticancer drugs currently in use. for oxaliplatin, the dose-limiting toxicity comes from sensory [Cancer Res 2009;69(11):4742–9] neuropathy (3), a characteristic of all DACH-containing platinum derivatives. Alkylating agents are another class of drugs with an Introduction important role in cancer treatment. Each alkylating agent has its own specific associated toxicity and will not be discussed Aside from the cancer itself, the biggest enemy that most individually here. Instead, listed here are some toxicities common cancer patients still face, while undergoing treatment with to alkylating agents as a class: hematopoietic toxicity, gastroin- chemotherapy, is the high toxicity (or side effects) associated testinal toxicity, gonadal toxicity, pulmonary toxicity, alopecia, with the various anticancer drugs. The therapeutic index (TI), teratogenicity, carcinogenesis, and immunosuppression. Among defined as a ratio of the maximum tolerated dose (MTD) to the these, the usual dose-limiting toxicity for an alkylating agent is its effective dose, of each anticancer drug provides a quantitative hematopoietic toxicity. Finally, topoisomerase-interactive agents assessment of its relative toxic and therapeutic effects. As most comprise yet another class of chemotherapeutic drugs that have chemotherapeutic agents clinically used today have very narrow increasingly gained attention from clinical oncologists for their TI ranges (f1), patients receiving chemotherapy often suffer unique mechanisms of action. Topotecan, one of these top- greatly from many toxic side effects while receiving treatment at oisomerase-interactive agents, is indicated in the second-line therapeutic dose levels. The various anticancer agents are treatment of advanced refractory ovarian (7) and small cell lung characterized by differences in grades and types of toxicity, cancers (8, 9), and it also has been active in the treatment of influenced by the specifics of their pharmacokinetics and hematologic malignancies, including myelodysplastic syndromes pharmacodynamics. For example, 5-fluorouracil (5-FU) is one of and multiple myeloma (10). The dose-limiting toxicity of this the most commonly used chemotherapeutic agents for the agent is myelosuppression. Although topotecan has been com- systemic and palliative treatment of patients with cancers arising bined with a variety of other treatments, including radiation, from the gastrointestinal tract, breast, head, and neck. In the cisplatin, paclitaxel, and doxorubicin, in clinical trials, none of these combinations has achieved any routine use in clinical oncology. This may be due, in part, to the frequent myelosup- Requests for reprints: Zhisong Cao, CHRISTUS Stehlin Foundation for Cancer pressive toxicity of topotecan that has made it difficult to Research, 1918 Chenevert Street, Houston, TX 77003. Phone: 713-756-5750; Fax: 713- combine in high doses with other bone marrow–suppressive 756-5783; E-mail: [email protected]. I2009 American Association for Cancer Research. agents (11). Irinotecan, another topoisomerase-interactive agent, doi:10.1158/0008-5472.CAN-08-4452 is indicated as a single agent or in combination with 5-FU and Cancer Res 2009; 69: (11). June 1, 2009 4742 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst May 19, 2009; DOI: 10.1158/0008-5472.CAN-08-4452 A Novel Anticancer Agent CZ48 Figure 1. The reaction pathway for synthesizing CZ48. leucovorin in treating patients with colorectal cancers (12, 13) and advanced colorectal cancer. The S-configured lactone form of has also been found to be active in small cell lung cancer when camptothecin molecule is thought to be required for antitumor given in combination with cisplatin. This combination has also activity. The carboxylate form is only 10% as active as the been found to be active in non–small cell lung cancer (10). The lactone form as an anticancer agent. The two forms of the dose-limiting toxicities of irinotecan are neutropenia and delayed- molecule exist in equilibrium in aqueous solution. This onset diarrhea; the uses of irinotecan in clinical oncology are thus equilibrium is pH dependent. The lactone is not stable in the limited. Other anticancer agents, including recently marketed body of mammals at the slightly basic physiologic pH (7.4). Even Erbitux and Avastin, occasionally used by oncologists for specific worse, in man, the human serum albumin has a high affinity for treatments, are likewise limited due to their associated toxicities. the carboxylate form of the molecule (17, 18), binding it and Thus, the biggest challenge is still for cancer researchers and moving the equilibrium between it and the lactone form to the À clinical oncologists to find better chemotherapeutic agents with right (CPTX CPT ). Because of this, when we treated human wider TIs. tumors as xenografts in nude mice with camptothecin or its As a class, the camptothecins have a broad spectrum of derivatives such as 9-nitrocamptothecin and 9-aminocamptothe- anticancer activity. Wall and colleagues (14) isolated and purified cin, we obtained excellent results (19, 20), but when we went the molecule from the Chinese tree Camptotheca acuminate in into human clinical trials, the complete responses became 1966; they subsequently tested the compound against mouse sporadic (21). This is no surprising because in mice 50% of leukemia L1210 system and found that the compound was the CPT was in the active lactone form (22), whereas in man the active. However, the early human clinical trials in 1970s failed to percentage dropped to 3% to 5%. prove the true values of the compound for clinical oncology, In efforts of finding better camptothecin analogues for instead showed severe, unpredictable toxicities, such as hemor- treatment, we previously synthesized many different camptothecin rhagic cystitis. The trials were accordingly halted. The interest in estersbyattachinganesterchaininpositionC-20and this family of compounds was renewed in the mid-1980s by the subsequently evaluated these compounds (23, 24). The treatment finding that the molecular target of camptothecins was the of human tumors grown as xenografts in nude mice with our nuclear enzyme topoisomerase I (15). At approximately the same synthetic camptothecin esters was effective and toxicity in mice time, new water-soluble derivatives such as topotecan and was minimal (25, 26). Based on these results, we went deeper in the irinotecan were prepared and biologically evaluated. The direction and successfully prepared crystalline camptothecin-20(S)- subsequent clinical evaluations of these two compounds showed O-propionate hydrate (CZ48). We