Antitumor drug cross-resistance in vivo in a murine P388 leukemia resistant to ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - ylcarbamate 2-hydroxyethanesulfonate hydrate (NSC 370,147) 370147.

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7- ylcarbamate 2-hydroxyethane-sulfonate hydrate (NSC 370147) is a potent mitotic inhibitor, which has provided the basis for a candidate for clinical trial. As observed with clinically useful drugs, the development of clinical resistance to NSC 370147 will probably be encountered. Information concerning resistance to NSC 370147 should aid in the design of strategies for the optimal clinical use of the drug. A P388 leukemia resistant to NSC 370147 (P388/NSC 370147) was isolated and its in vivo cross-resistance profile was determined. The P388/NSC 370147 line was cross-resistant to vincristine but was not cross-resistant to doxorubicin, etoposide, cisplatin, melphalan, methotrexate, or 5-fluorouracil. This information plus other in vivo cross-resistance data [Waud et al. (1990) Cancer Res 50: 3239] suggests that NSC 370147 may be useful in non-cross-resistant combinations with doxorubicin, melphalan, cisplatin, or methotrexate. The lack of cross-resistance of P388/NSC 370147 to doxorubicin and etoposide shows that resistance to NSC 370147 does not involve multidrug resistance and suggests that the mdr1 gene is not involved in resistance to NSC 370147.

Antitumor activity of ethyl 5-amino-1,2-dihydro-2-methyl-3-phenyl-pyrido [3,4-b]pyrazin-7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) against selected tumor systems in culture and in mice.

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin- 7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) was evaluated for antitumor activity against a spectrum of tumor systems in culture and in mice. NSC 370147 was cytotoxic to a variety of mouse and human cell lines at nanomolar concentrations. The compound exhibited good in vivo antitumor activity against several murine tumors (P388 and L1210 leukemia, colon 11/A and 36, mammary 16/C, and M5076 sarcoma). Activity was largely independent of route of administration but favored a prolonged treatment schedule. NSC 370147 was as active against murine leukemia sublines resistant to Adriamycin, amsacrine, vincristine, melphalan, cisplatin, methotrexate, and CI-920 (a topoisomerase II inhibitor) as against the corresponding parental lines. Only the 1-beta-D-arabinofuranosylcytosine-resistant P388 subline exhibited any cross-resistance to NSC 370147. NSC 370147 has a spectrum of activity similar to that of vincristine and, unlike vincristine, is active against multidrug-resistant cell lines. Therefore, NSC 370147 is a candidate for clinical trial because of its favorable activity compared to vincristine, its effectiveness against multidrug-resistant cells, and its retention of activity for p.o. administration.

Pharmacokinetic and metabolism studies of two novel 1-deaza-7,8-dihydropteridines in mice.

The disposition of two 1-deaza-7,8-dihydropteridines, NSC 269416 and NSC 350386, was studied in mice dosed iv. After dosing with 25 mg/kg of NSC 269416, serum levels fell in two phases with half-lives of 3.1 and 32 min. Highest levels were in liver, kidney, spleen, lungs, and small intestines; little compound was detected in brain, muscle, or fat. Although no metabolites were detected in serum or tissues, four metabolites, but no parent compound, were present in urine. After administration of 7 mg/kg of NSC 350386, serum levels fell with apparent half-lives of 4.3 (alpha-phase) and 49 min (beta-phase). At most times of analysis, liver, kidney, spleen, lung, brain, fat, and small intestines had similar concentrations of the compound. In 24 hr, less than 5% of the dose was excreted into urine unchanged. Analyses of collected urinary products indicated that, in vivo, NSC 350386 was metabolically hydroxylated and conjugated with glucuronic acid and also cleaved, a process involving removal of the ethoxycarbonyl group.

Inhibition of mitosis and anticancer activity against experimental neoplasms by ethyl 5-amino-1,2-dihydro-3-[(N-methylanilino)methyl]-pyrido[3,4-b]pyrazin-7-ylcarbamate (NSC 181928).

Ethyl 5-amino-1,2-dihydro-3-[N-methylanilino)methyl]pyrido[3,4-b]pyrazin-7-ylcarbamate (NSC 181928) is reported to be active against several experimental neoplasms. The experimental data obtained in the present study indicate that it causes the accumulation of cells at mitosis with both cultured cells and ascites cancer cells in vivo. This effect was observed with L1210, P388, colon cancer 26, colon cancer 38, and H.Ep. 2 cells in culture and with L1210 cells and P388 cells in mice. The agent was also active in vitro and in vivo against a line of leukemia P388 cells that are resistant to vincristine.