Reference

Optimization of high-dose methotrexate with leucovorin rescue therapy in the L1210 leukemia and sarcoma 180 murine tumor models

Optimization of high-dose methotrexate with leucovorin rescue therapy in the L1210 leukemia and sarcoma 180 murine tumor models. Sirotnak, Francis M.; Moccio, Donna M.; Dorick, Diane M. (Mem. Sloan-Kettering Cancer Cent., New York, N. Y., USA). Cancer Res., 38(2), 345-53 (English) 1978. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacodynamics) An anal. of dose and schedule dependence for calcium leucovorin [1492-18-8] rescue during high-dose methotrexate (I) [59-05-2] therapy of ascitic forms of L1210 leukemia and Sarcoma 180 is reported. Schedules with very delayed low-dose leucovorin rescue following LDs of I were highly effective in preventing toxicity and achieved a pronounced antitumor effect in both ascites tumor models. Best results were obtained on a schedule of I (400 mg/kg s.c.) followed 16 to 20 h later by Ca leucovorin (12 mg/kg s.c.) given once every 2 h for a total of 5 doses. Progressive increases in the Ca leucovorin dosage on any schedule reduced both toxicity and the antitumor effect of I in each model. Following a single course of therapy, essentially no toxicity was obsd., and the antitumor effects were 2-fold (L1210 leukemia) and 4-fold (Sarcoma 180) greater than a single, max. tolerated dose (24/kg s.c.) of I alone. An increase in the I dosage to 80 mg/kg s.c. with or without an increase in Ca leucovorin dosages on the same schedule did not appreciably increase the antitumor effect obsd. Two courses of high-dose I (400 mg/kg s.c.) with leucovorin rescue (24 mg/kg s.c. 16, 20, and 24 h after drug) given with an 8-day interval between courses doubled the total antitumor effect in each model with no substantial increase in toxicity and gave long-term survivors with Sarcoma 180. The results, overall, are in close agreement with the prior prediction for schedule and dose dependence made on the basis of related pharmacokinetic and biochem. studies in murine tumor models.

Vinca alkaloid skin toxicity: antidote and drug disposition studies in the mouse

Vinca alkaloid skin toxicity: antidote and drug disposition studies in the mouse. Dorr, Robert T.; Alberts, David S. (Coll. Med., Univ. Arizona, Tucson, AZ 85724, USA). JNCI, J. Natl. Cancer Inst., 74(1), 113-20 (English) 1985. CODEN: JJIND8. ISSN: 0198-0157. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 2, 18 A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) [865-21-4] and vindesine (VDS) [53643-48-4]. With vincristine (VCR) [57-22-7] only about 70% of mice developed dose-dependent ulceration. On an equal wt. basis, VCR proved to be more toxic than either VBL or VDS. Effective local intradermal antidotes to VBL, VDS, and VCR included hyaluronidase [9001-54-1], normal saline, and calcium leucovorin [1492-18-8]. Mild, topical skin heating reduced VCR ulceration. In contrast, diphenhydramine [58-73-1] and sodium bicarbonate [144-55-8] were ineffective as local antidotes. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR. Hydrocortisone [50-23-7], vitamin A [11103-57-4] topical cream, and isoproterenol [7683-59-2] increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharmacokinetic disposition from the skin and adherent panniculus carnosus muscle. [+H]VBL exhibited two phases of elimination: a rapid early phase and a prolonged terminal phase. The application of heat increased the distributive, early phase by 0.5-2.5 h and did not enhance the terminal elimination of the drug from skin. Intradermal hyaluronidase reduced the area under the ulceration multiplied by the time curve to 1/7th the control value, the peak [3H]VBL skin concn. to 50% the control value and the terminal [3H]VBL t1/2 in skin to 1/3rd the control level. These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasations.