Pre-Clinical Antitumor Activity of 9-Nitrocamptothecin (9NC) in Proprietary IDD-P™ and
IDD-D™ Formulation
Howard Sands, Awadhesh K. Mishra, Beth A. Hollister, Terri A. Alford, Robin Ball, Shih-Fong Chen, SuperGen,
Wilmington, DE; RTP Pharma Inc.,, Nuns Island, PQ, Canada; Piedmont Research Center, Morriville, NC.
9-Nitrocamptothecin (9NC), a water-insoluble camptothecin, is in Phase III trials in patients with pancreatic cancer. Only an
oral formulation of the drug is currently available for clinical use. Intravenous administration might decrease GI tract toxicity and
modify drug disposition. It would also permit regional perfusion for high-dose chemotherapy restricted to a tumor site. We have
evaluated two I.V. formulations, IDD-P™-9NC and IDD-D™-9NC, to determine whether 9NC has parenteral
activity in nude mice bearing human tumors. The IDD-P™ and IDD-D™ formulations of 9NC were prepared by
RTP Pharma Inc. using their proprietary IDD™ technology. Athymic nude mice bearing human A375 melanoma were
treated intravenously with 3 and 1.5 mg/kg of 9NC as the IDD-P™ formulation and 2 and 1 mg/kg of 9NC as the
IDD-D™ formulation on two cycles of a five-days-on and two-days-off schedule. The antitumor activity was compared
to the activity of 9NC given orally and to the activity of two clinically available camptothecin analogs, CamptosarÒ and
HycamtinÒ , at their optimal preclinical doses and schedules. The IDD-P™-9NC formulation demonstrated outstanding
antitumor activity: partial or complete tumor shrinkage in some animals and 97-99% tumor growth inhibition in the remaining
animals. The IDD-D™-9NC formulation was less active, inhibiting the growth of A375 tumor to a lesser degree (87%) at
the maximal tolerated dose (2 mg/kg). The activity of IDD-P™-9NC was equivalent to that of the oral formulation of
9NC and superior to the activity of CamptosarÒ and HycamtinÒ . In summary, 9-nitrocamptothecin formulated in
IDD-P™ has outstanding parenteral antitumor activity against human melanoma xenografts. We are investigating whether
the I.V. activity of IDD-P™-9NC extends to other human tumor xenografts and how its spectrum of activity compares to
that of the oral preparation. |
