Phase I and Pharmacology Study of Camptothecin-20-O-Propionate Hydrate (CZ48) in Patients With Solid Tumors or Lymphoma

CZ48 is an analog of the topoisomerase I inhibitor Camptothecin (CPT). CPT is an alkaloid extracted from the Chinese tree, Camptotheca acuminata. Only the S isomer (the natural form) is biologically active. The intact E lactone ring, which tends to be preserved in an acid environment, is essential for anti-tumor activity. Moreover, the open lactone ring moiety tends to promote toxicity [1-3]. In phase I and II trials conducted from 1970-1972 with the sodium salt of CPT (later shown to be largely inactive) toxicities included myelosuppression, diarrhea and cystitis [2, 3].

With the observation in 1984 that the mechanism of action of CPT was through topoisomerase I inhibition [1], renewed interest in the drug led to the development of a variety of analogs, some of which had higher potency than the parent drug. Some derivatives are water soluble such as Camptosar® (irinotecan, CPT¬-11) and Hycamptin® (topotecan), which are currently approved for use in the USA for colon and ovarian cancers, respectively. Studies have shown that substitutions at the C-9 and C- 10 positions enhance activity, and may confer water solubility. In general, analogs that are water-soluble have reduced anti-cancer activity in preclinical models.

The water-insoluble native camptothecin (CPT) caused diarrhea, which proved to be the dose limiting toxicity. Measurements demonstrated very little closed lactone ring CPT in the plasma of subjects receiving this compound [4]. This was later explained by the demonstration that CPT binds to human albumin, an action which promotes opening of the lactone ring [5]. Mouse albumin is much less efficient in this activity, hence explaining the greater antitumor activity observed in mice models.

In contrast to CPT, CZ48 incubated in vitro with human plasma and studied in vivo maintains a substantial closed lactone ring concentration in the plasma. It appears to act as a pro-drug. The removal of the side chain by endogenous esterases liberates the active drug, CPT. Malignant cells have a high esterase content and are rapidly transforming the pro-drug into the active parent drug. Preclinical studies suggest retention of anti-cancer activity and reduction in toxicity, probably because the pro-drug in the systemic circulation has no or little activity. Therefore, delivery of higher concentrations of closed lactone ring CPT analog inside the tumor cells should potentiate the anti-tumor activity. This study offers an opportunity to evaluate this hypothesis.

• OVERVIEW OF NONCLINICAL TESTING STRATEGY