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Relation between 9-Aminocamptothecin Systemic Exposure and Tumor Response in Human Solid Tumor Xenografts¹

Departments of Pharmaceutical Sciences [M. N. K., A. K. S., S. K. H., C. F. S.] and Molecular Pharmacology [P. J. H., P. J.C., L. B. R.], St. Jude Children’s Research Hospital, and Department of Pharmacology [P. J. H.] and The Center for Pediatric Pharmacokinetics and Therapeutics [P. J. H., C. F. S.], University of Tennessee, Memphis, Tennessee 38105

	ABSTRACT

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9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with activity against xenografts from childhood solid tumors; however, clinical trials with this compound have been disappointing, resulting in discontinuation of further development. The objectives of this study were to evaluate the antitumor activity of 9-AC in a panel of pediatric solid tumor xenografts and to relate the 9-AC lactone systemic exposure, defined as area under the concentration time curve (AUC), to the antitumor dose associated with tumor regression in the xenograft model. We evaluated protracted administration of i.v. and oral therapies (daily times 5) for 1, 2, or 3 weeks and for 1 or 3 cycles. The minimum effective dose of 9-AC causing objective regression of advanced tumors was determined for each schedule. 9-AC lactone plasma concentration-time profiles associated with the lowest dose achieving complete and partial responses for each xenograft were then determined for each regimen. Tumors were highly sensitive to 9-AC therapy, but the systemic exposure required for antitumor effect is in excess of that achievable in patients.

	INTRODUCTION

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9-AC,³ is a semisynthetic of the plant alkaloid camptothecin with greater aqueous solubility than the parent compound (1) . Camptothecin, and derivatives such as 9-AC, covalently trap topoisomerase I on DNA after the enzyme has introduced a single strand nick. In cells replicating DNA, this could result in a collision between the complex and the advancing replication fork, leading to a double-strand DNA break. It is considered that generation of this break initiates a cascade leading to apoptosis (2) .

9-AC has demonstrated a spectrum of activity in animal models with transplantable solid tumors including cancer of the colon, lung, breast, and malignant melanoma xenografts (3 , 4) . However, clinical trials with this compound have been quite disappointing, resulting in its discontinuation from further clinical development (5 , 6) . In contrast, two other camptothecin derivatives, topotecan and irinotecan, have shown significant clinical utility and are now approved for use by the Food and Drug Administration.

Whereas the proportion of the topotecan lactone is maintained at 40–50% in plasma, only 10% of 9-AC exists in the lactone form in human plasma. This contrasts with a far higher proportion of 9-AC lactone in plasma from mice. It has been suggested that this interspecies difference in lactone to carboxylate equilibrium accounts for the observed responsiveness of human tumors growing in mice compared with the nonresponsiveness of human tumors growing in patients (7) . However, no one has assessed the 9-AC systemic exposure at doses associated with cytotoxicity in the xenograft model.

In previous studies, we have shown that the systemic exposure to clinically effective and tolerated doses of topotecan and irinotecan in children with solid tumors is similar to that resulting in antitumor effects observed in the xenograft models (8) . These data have been used in the design of clinical trials of these agents in children with recurrent solid tumors (9 , 10) . At initiation of this study, the activity of 9-AC in pediatric solid tumors was unknown, as was the extent of systemic exposure that would be necessary for an objective response in the xenograft model. Accordingly, the objectives of the present study were to evaluate the antitumor activity of 9-AC in a panel of pediatric solid tumor xenografts and to relate the 9-AC lactone systemic exposure, defined as the AUC, to the antitumor dose associated with tumor regression in the xenograft model. These data will be important to understanding the lack of efficacy of 9-AC in published clinical trials.

	MATERIALS AND METHODS

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Immune Deprivation of Mice.
Female CBA/CaJ mice (Jackson Laboratories, Bar Harbor, MD), 4 weeks of age, are immune-deprived by thymectomy, followed 3 weeks later by whole-body irradiation (1200 cGy) using a ¹³⁷Cs source. Mice received 3 x 10⁶ nucleated bone marrow cells within 6–8 h of irradiation. Tumor pieces of 3 mm³ are implanted in the space of the dorsal lateral flanks of the mice to initiate tumor growth. Tumor-bearing mice are randomized into groups of seven prior to therapy.

Tumor Lines.
Tumor lines have been described previously. HC₁ is a moderately differentiated adenocarcinoma of the colon derived from an adult patient (11) . NB-1771 and NB-SD are N-MYC amplified stage D childhood neuroblastomas (12) , and Rh12 is an embryonal rhabdomyosarcoma (13) . The sensitivity of each of these tumors to topotecan (14) and irinotecan (11 , 12) has been reported previously. Once established as xenografts, further transplantations of neuroblastoma tumors were from mouse to mouse, rather than from cell culture to mouse. For chemotherapy studies, all tumors were used within six passages of their engraftment in mice. Each tumor grew routinely in >95% of recipient mice, and all retained human origin as determined by karyotype.

Growth Inhibition Studies.
Mice bearing bilateral s.c. tumors each received the agent when tumors were approximately 0.20–1 cm in diameter. The procedures have been reported previously (15) . Briefly, two perpendicular diameters were determined at 7-day intervals using digital Vernier calipers interfaced with a Macintosh computer. Tumor volumes were calculated assuming tumors to be spherical using the formula [(/6) x d³ ], where d is the mean diameter, and mice were followed for up to 12 weeks after starting treatment.

Tumor Response.
For individual tumors, PR was defined as volume regression >50% but with measurable tumor at all times. CR was defined as the disappearance of measurable tumor mass at some point after initiating therapy. Maintained complete response was CR without tumor regrowth within the study time frame (12 weeks). The minimum effective 9-AC dose achieving objective response (CR and PR) for individual xenograft lines (MEDOR) was defined as the minimum dose of 9-AC producing CR or PR in all tumors within the treatment group, respectively.

Formulation and Administration.
9-AC as a colloidal dispersion was provided by Pharmacia and Upjohn and was reconstituted as directed. The drug was administered i.v. on the following schedules: (dx5)1; (dx5)2; or (dx5)3. Where indicated, cycles of therapy were repeated every 21 days over 8 weeks for the (dx5)1 and (dx5)2 treatments or every 28 days for the (dx5)3 schedule. Either one or three cycles of treatment were administered. In separate cohorts of mice, the drug was administered by oral gavage using the same schedules.

Drug Administration and Sample Collection.
The disposition of 9-AC was evaluated after a single 9-AC dose of 1.25 mg/kg administered by direct injection (duration of infusion <1 min) into a lateral tail vein or by oral gavage. Pharmacokinetic studies were performed in nontumor bearing-mice and mice bearing HC₁, NB-1215, and Rh12 tumors. Heparinized blood samples (1 ml) were collected prior to the dose and at 0.25, 0.5, 1, 1.5, 2, 4, and 6 h after oral 9-AC, and prior to the dose and at 0.25, 0.5, 1, 2, 4, and 6 h after i.v. 9-AC. Blood samples were immediately centrifuged at 5.5 x g for 2 min on a tabletop centrifuge. The plasma was separated, and the proteins precipitated by the addition of 600 µl of cold methanol (-30°C) to 200 µl of plasma, followed by vigorous agitation with a vortex mixer, and centrifugation again at 5.5 x g for 2 min. The supernatant was decanted and stored at -70°C until analysis.

9-AC HPLC Assay.
9-AC plasma concentrations were determined using a modification of the method of Takimoto et al. (16) . Briefly, after the plasma sample was processed as described above, it was manually injected onto a 5 µM Ultrasphere ODS (Beckman, Fullerton, CA) analytical column (4.6 mm x 25 cm). The samples were eluted with a mobile phase consisting of acetonitrile:methanol:0.1 M ammonium acetate, pH 5.5 (25:10:65, v/v/v), at a flow rate of 1.0 ml/min. Because 9-AC has poor fluorescence relative to the parent compound camptothecin, we used postcolumn acidification to protonate the C-9 amino group and enhance drug fluorescence, which is optimal at pH 1.7–2.3. Postcolumn acidification was accomplished by in-line mixing with 0.3 M aqueous trifluoroacetic acid (flow rate, 0.3 ml/min) prior to fluorescence detection. The emission and excitation wavelengths were 352 and 418 nm, respectively. All calibrators and controls for the xenograft studies were prepared in murine plasma (Hill Top Lab Animals, Inc., Scottdale, PA).

Pharmacokinetic Analysis.
Noncompartmental methods (WinNonlin Professional version 3.0; Pharsight, Cary, NC) were used to analyze both the i.v. and oral 9-AC plasma concentration time data from this study. The AUC was calculated by the log-linear trapezoidal rule to the last measurable data point. The elimination rate constant (K_e) determined by regression analysis of the terminal phase of the plasma concentration-time curve was used to extrapolate the AUC to infinity (AUC₀). The area under the first moment curve (AUMC) and mean residence time (MRT) were also determined (17) . For i.v. dosing, the clearance and volume of distribution at steady-state were determined, and for oral dosing, the apparent clearance and volume of distribution were determined.

	RESULTS

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Antitumor Effect of 9-AC Administered i.v.
Schedule-dependent activity of 9-AC was evaluated in each of four xenograft models. The MEDOR for advanced tumors was determined for each schedule (Table 1) . When 9-AC was administered i.v. daily for 5 days for a single course, [(dx5)1]1, no PRs were obtained at dose levels associated with acceptable toxicity (i.e., weight loss <20%). Thus, when 9-AC was administered as a single course on a [(dx5)1]1 schedule, the minimum effective daily dose was 1.5 mg/kg. Similarly, no PRs were noted in HC₁, NB-1771, or NB-SD when the 5-day course was repeated every 21 days for three cycles, [(dx5)1]3. Using the 5-day schedule on 2 consecutive weeks for one cycle, [(dx5)2]1, resulted in objective regressions (HC₁ and Rh12) at a daily dose of 1 mg/kg. This dose was toxic to mice bearing NB-1771 tumors. In Fig. 1 , we depict the effect of administering three cycles of therapy, where 9-AC was given i.v. for [(dx5)1]3, [(dx5)2]3 every 21 days, or [(dx5)3]3 every 28 days for HC₁ colon tumors. Both [(dx5)2]3 and [(dx5)3]3 schedules resulted in regressions at dose levels of 0.36 and 0.29 mg/kg, respectively. In contrast, 1.5 mg/kg [(dx5)1]3 failed to prevent tumor progression. The cumulative doses administered for [(dx5)1]3, [(dx5)2]3, and [(dx5)3]3 schedules were 22.5, 10.8, and 13.0 mg/kg, respectively. Very similar results were obtained with NB-1771 neuroblastoma xenografts, further indicating marked schedule-dependent antitumor activity of 9-AC (Fig. 2) . Responses of NB-SD xenografts to decreasing doses of 9-AC using the [(dx5)2]3 schedule are shown in Fig. 3 . Complete regressions were obtained at 0.66 mg/kg, with some PRs at 0.44 mg/kg and only growth retardation at 0.29 mg/kg.

View larger version (39K): [in this window] [in a new window]   Fig. 1. Responses of HC1 colon adenocarcinoma xenografts to i.v. treatment with 9-AC. Mice received three cycles of therapy given every 21 days [for (dx5)1 and (dx5)2 schedules] or every 28 days [for the (dx5)3 schedule] as described in "Materials and Methods." Tumor volumes were determined every 7 days. Each curve represents growth of an individual tumor.

View larger version (32K): [in this window] [in a new window]   Fig. 2. Responses of NB-1771 neuroblastoma xenografts to i.v. treatment with 9-AC. Mice received three cycles of therapy given every 21 days [for (dx5)1 and (dx5)2 schedules] or every 28 days [for the (dx5)3 schedule] as described in "Materials and Methods." Tumor volumes were determined every 7 days. Each curve represents growth of an individual tumor.

View larger version (39K): [in this window] [in a new window]   Fig. 3. Responses of NB-SD neuroblastoma xenografts treated i.v. with different dose levels using the (dx5)2 schedule for three cycles. Tumor volumes were determined every 7 days. Each curve represents growth of an individual tumor.

View larger version (38K): [in this window] [in a new window]   Fig. 4. Responses of NB-1771 neuroblastoma xenografts treated p.o. with different dose levels using the (dx5)2 schedule for three cycles. Tumor volumes were determined every 7 days. Each curve represents growth of an individual tumor.

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View larger version (8K): [in this window] [in a new window]   Fig. 5. The 9-AC plasma concentration versus time plot after i.v. 9-AC for non-tumor-bearing animals () and NB-1215 () tumor-bearing animals.

View larger version (7K): [in this window] [in a new window]   Fig. 6. The 9-AC plasma concentration versus time plot after oral 9-AC for non-tumor-bearing animals () and NB-1215 () tumor-bearing animals.

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	DISCUSSION

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As with other camptothecin analogues, 9-AC has schedule-dependent antitumor activity. As the schedule of 9-AC administration was extended from [(dx5)1]3 to 2 weeks [(dx5)2] every 21 days or 3 weeks [(dx5)3] every 28 days, greater antitumor activity was observed. Although the daily dose for the three xenograft lines tested with the [(dx5)3] schedule was somewhat lower than for the [(dx5)2] schedule, the cumulative dose needed to attain an antitumor response was lower in the [(dx5)2] group (i.e., 13.0 versus 10.8 mg/kg, respectively).

The MEDOR of all tumors in a treatment group in our studies varied from 0.29 to 1.5 mg/kg/dose administered i.v. This range was dependent upon the administration schedule that was used. Previous studies examining 9-AC in the xenograft model include an evaluation by Giovanella et al. (3) . Briefly, 9-AC at a dose of 12.5 mg/kg was administered s.c. into mice bearing HT-29 colon cancer xenografts twice weekly for 3–6 weeks and resulted in >90% reduction in tumor volume. Additionally, Pantazis et al. (19) injected 4 mg/kg 9-AC i.m. twice weekly into mice bearing BRO melanoma xenografts and observed that the drug-treated mice were virtually free of tumor after 40 days. However, no pharmacokinetics results from these studies are available for comparison with the present study.

Numerous trials of 9-AC have been conducted in adults, and the results of these are summarized in Table 7 . Various dosing regimens, schedules, and routes of administration have been evaluated in these clinical trials to optimize antitumor activity and minimize toxicity. However, the antitumor responses have been very disappointing at doses that have led to unacceptable toxicities, primarily myelosuppression. Even with the addition of growth factor support, which decreased the duration and severity of myelosuppression, little increase in antitumor activity was observed at the highest 9-AC doses.

The antitumor responses observed after oral 9-AC were similar to those observed after i.v. administration. Although the dose associated with the oral MEDOR was higher than that required for i.v. administration, tumor regression was observed in a schedule-dependent manner, and these responses were induced at acceptable levels of toxicity to the mouse. In a Phase I trial, Mani et al. (21) administered oral 9-AC (formulated in PEG-1000) to 16 adult patients with a variety of solid tumors. The dosages ranged from 0.06 to 0.2 mg/kg daily for 5 days every 2 weeks. No objective responses or cumulative toxicities were observed; however, the investigators concluded that the formulation was not suitable for further development because of poor bioavailability and variable elimination. These clinical characteristics of oral 9-AC administration, taken together with the results from the xenograft model, would predict that it would not be possible to attain the 9-AC systemic exposure necessary for antitumor responses.

In the only published trial in children, Langevin et al. (22) administered 9-AC to children with recurrent solid tumors by a 72-h infusion every 21 days. The 9-AC disposition was analyzed at doses of 36, 43, and 62 µg/m²/h (22) , and the 9-AC lactone AUC values for the course reported were 233, 169, and 493 ng/ml·h, respectively. The authors reported one PR, and as in the adult Phase I trials, neutropenia and thrombocytopenia were dose limiting. As a consequence, the authors recommended a Phase II dose of 52 µg/m²/h on this schedule.

The schedule of 9-AC administration associated with the most antitumor efficacy in these xenograft models was dailyx5 for 2 weeks repeated every 21 days [(dx5)2]3. On the basis of the data presented in Table 5 , the dose required for antitumor activity on this schedule ranged from 0.36 to 0.66 mg/kg/day. The 9-AC lactone daily systemic exposure corresponding to these doses ranged from 69 to 158 ng/ml·h. Thus, the cumulative 9-AC lactone systemic exposure associated with antitumor efficacy in the xenograft model ranged from 690 to 1580 ng/ml·h for the course of therapy. This is compared with the maximum tolerated 9-AC systemic exposure from either adult or pediatric clinical trials of continuous infusion 9-AC of 126 or 493 ng/ml·h. Thus, it is not surprising that few antitumor responses have been observed with 9-AC because hematopoietic toxicity limits the ability of patients to tolerate the extent of 9-AC systemic exposure that is associated with antitumor response in the xenograft model.

In summary, we have shown that 9-AC has antitumor activity in a panel of pediatric solid tumors when administered in a schedule-dependent manner. Antitumor responses were noted in the xenograft model at 9-AC doses that were associated with acceptable toxicity. However, 9-AC lactone systemic exposure required to induce tumor responses in the xenograft were greater than the plasma systemic exposures reported at maximally tolerated 9-AC doses in patients. These data support the concept of determining systemic exposures associated with MEDOR in mice bearing human tumor xenografts. Although clinical trials using 9-AC have been disappointing, our results demonstrate the potential usefulness of determining systemic exposures necessary to achieve an antitumor effect. By deriving preclinical data relating systemic exposure to antitumor activity in xenograft models, informed decisions might be made regarding the clinical development of new agents for the treatment of childhood and adult cancers.

	ACKNOWLEDGMENTS

 
We thank Yuri Yanishevshi for his excellent technical support.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by a grant from Pharmacia and Upjohn Pharmaceutical Co., USPHS Award CA 23099, Cancer Center Support Grant CA 21765, and American Lebanese Syrian Associated Charities.

² To whom requests for reprints should be addressed, at Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-3665; Fax: (901) 525-6869; E-mail: clinton.stewart{at}stjude.org

³ The abbreviations used are: 9-AC, 9-amino-20(S)-camptothecin; AUC, area under the plasma concentration-time curve; PR, partial response; CR, complete response; MEDOR, minimum effective dose of 9-AC achieving objective response; (dx5)1, daily x 5 for 1 week; (dx5)2, daily x 5 for 2 consecutive weeks; (dx5)3, daily x 5 for 3 consecutive weeks.

Received 5/ 8/00; revised 9/27/00; accepted 10/ 5/00.

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