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Odwyer PJ , Moyer JD , Suffness M , Harrison SD , Cysyk R , Hamilton TC , Plowman J
Antitumor-Activity and Biochemical Effects of Aphidicolin Glycinate (Nsc-303812) Alone and in Combination with Cisplatin in-Vivo
Cancer Research. 1994 Feb 1;54(3) :724-729
PMID: ISI:A1994MU67700023   
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Abstract
Aphidicolin, an inhibitor of DNA polymerases alpha and delta, is cytotoxic in vitro against tumor cells. The poor solubility of aphidicolin has led to the development of aphidicolin glycinate (AG; NSC 303812), a water soluble ester currently in early clinical trials. The antitumor activity of AG was investigated in a series of transplantable murine tumors in vivo. The drug demonstrated activity against the i.p. implanted B16 melanoma, producing maximum increased life spans of 75% following i.p. administration every 3 h for three doses on days 1-9. Treatment schedules involving both single injections per day on days 1-9 and multiple injections per day on days 1, 5, and 9 were less effective, indicating that this antitumor activity is schedule dependent. Similarly, greater activity was observed against the i.p. M5076 sarcoma when three daily injections were given on days 1-9 (57% increased life span) than with a single injection either on days 1-9 (36% increased life span) or on days 1, 5, 9, and 13 (inactive). Further scheduling studies in the s.c. M5076 sarcoma model showed that a 7-day infusion was superior to both a 24-h infusion and a 7- day course of three bolus treatments per day. On the assumption that DNA polymerase inhibition is the basis for this antitumor activity, inhibition of DNA synthesis in BALB/c x DBA/2 F1 mice was investigated by measuring incorporation of [H-3]thymidine (20 muCi, i.v.) into DNA of spleen and jejunum. At 2 h after administration of AG, inhibition of DNA synthesis was dose dependent (median inhibitory dose, 60 mg/kg in both tissues) and was >99% at 300 mg/kg. The inhibition was rapid in onset: AG (100 mg/kg i.p.) produced maximal (>98%) inhibition in both tissues at 30 min. Recovery occurred in the intestine within 16 h; in spleen recovery was delayed to 24 h, and was followed by a rebound incorporation at 48 h (203%). A comparison of the inhibition of thymidine incorporation in tumor cells (B16 melanoma and P388 leukemia) and normal jejunum revealed no significant differences in the extent of inhibition or the rapidity of recovery in these tissues. The rapid recovery of DNA synthesis inhibition supports the use of prolonged infusion schedules in clinical trials, but the lack of evidence of selectivity for tumor cells suggests that AG may be of limited therapeutic value as a single agent. Thus, we evaluated AG in combination with cisplatin in an in vivo model of cisplatin refractory human ovarian cancer. In this model system, AG as a single agent had minimal activity whereas its use in bolus form at 30 mg/kg/dose every 3 h for 4 doses with cisplatin (5 or 8.3 mg/kg) at 90 min after the second AG injection was markedly superior to cisplatin alone. Furthermore, a continuous 7-day infusion of 150 mg/kg/day with cisplatin (8.3 mg/kg) on the second day of the AG infusion was equivalent in efficacy to the maximum tolerated dose of cisplatin (14 mg/kg). These data, in combination with information on the sustained levels of AG which may be achieved in patients support the clinical development of combination therapy with AG and cisplatin/carboplatin in platinum refractory patients.
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English Article MU677 CANCER RES