Spirogermanium: A new investigational drug of novel structure and lack of bone marrow toxicity
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Spirogermanium (NSC 192965) is a new metallic investigational anticancer drug of novel heterocyclic structure. Although its mode of action has not been fully elucidated, it appears that spirogermanium is not a phase or cell cycle specific drug and inhibits DNA, RNA and protein synthesis, the protein synthesis being the most susceptible to this agent. Spirogermanium has shown cytotoxic activity in vitro against several human tumor cell lines at concentrations (1 μg/ml) that were also found toxic to the cultured rat neurons. Although spirogermanium has no effect on normal bone marrow colony forming cells in mice, dogs, or man, it has revealed cytotoxic activity in vitro against human myeloid leukemia cell line K 562 at clinically achievable concentrations. These in vitro findings, indicating selective cytotoxic activity against leukemic cells suggest this drug as a candidate for clinical studies in acute and chronic leukemias.
Spirogermanium has revealed activity in vivo against intraperitoneally implanted Walker 256 sarcoma, 13762 mammary adenocarcinoma, and 11095 prostatic carcinoma in rats, but no antitumor activity in vivo was found in the murine tumors used in the past by the NCI screen (L 1210 and P 388 leukemia, B 16 melanoma, Lewis lung carcinoma).
Spirogermanium is remarkable for its lack of bone marrow toxicity confirmed in preclinical toxicology and clinical studies; moderate, predictable, and reversible CNS toxicity is dose-limiting. Activity in malignant lymphoma, ovarian cancer, breast cancer, large bowel cancer, and prostatic cancer was reported in the clinical studies. The drug is currently under clinical investigation against the wide spectrum of solid tumors and malignant lymphomas.
The dose of 80–120 mg/m2, given by 60′ infusion three times a week, is currently used and tolerated in Phase II clinical studies.
The recently introduced five days continuous infusion schedule has been also under clinical investigation and the doses of 250–300 mg/m2/day are recommended for Phase II studies.
Of interest are results reported in this paper of spirogermanium in vitro preferential activity against the resistant strains of Plasmodium falciparum at clinically achievable concentrations suggesting this drug as a possible new antimalarial agent of novel structure.
Key wordsspirogermanium anticancer agent antimalarial agent
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- 1.Slavik M, Elias L, Mrema J, Saiers JH: Laboratory and clinical studies of spirogermanium, a novel heterocyclic anticancer drug. Drugs Exptl Clin Res 8:379–385, 1982Google Scholar
- 2.Rice LM, Geschickter DF, Grogan CH: Spiranes III: azaspiranes and intermediates. J Med Chem 6:388–402, 1963Google Scholar
- 3.Rice LM, Sheth BS, Scott KR, Geschickter CF: Spirans XV: spirans derived from 3-trifluoromethyl cyclohexanone. J Med Chem 12:126–130, 1969Google Scholar
- 4.Rice LM, Sheth BS, Wheeler JW: Spirans XXI: Synthesis of silaazaspiro (4,5) decanes and silaazaspiro (5,5) undecances. J Heter Chem 10:737–741, 1973Google Scholar
- 5.Rice LM, Wheeler JW, Geschickter CF: Spirans XXII. Synthesis of 4,4-dialkyl-4-germacyclohexanone and 8,8-dialkyl-8-germaazaspiro (4,5) decanes. J Heterocyclic Chem 11:1041–1047, 1974Google Scholar
- 6.Rice LM, Slavik M, Schein P: Clinical brochure: Spirogermanium (NSC-192965). Prepared by the Georgetown University, Washington, DC, 1977Google Scholar
- 7.Screening data summaries. Drug Research and Development Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD, 1977Google Scholar
- 8.Woolley PV III, Maguire P, Fox P, Hoth D, Slavik M, Schein P: Studies with the antitumor agent spirogermanium. Proc Am Assoc Cancer Res 20:436, 1979 (abstract)Google Scholar
- 9.Schein PS, Slavik M, Symth T, Hoth D, MacDonald JS, Woolley PV: Phase 1 clinical trial of spirogermanium. Cancer Treat Rep 64:1051–1056, 1980Google Scholar
- 10.Hill BT, Whelan RDH, Bellamy AS, Whatley SA: Evaluation of in vitro lethal and biological effects of spirogermanium, a novel type of synthetic antitumor agent. Proc Am Assoc Cane Res 23:199, 1982 (abstract)Google Scholar
- 11.Hill BT, Whatley SA, Bellamy AS, Jenkins LY, Whelan RDH: Cytotoxic effects and biological activity of 2-Aza-8-germanspiro (4,5)-decane-2-propanamine-8, 8-diethyl-N, N-dimethyl dichloride (NSC 192965; Spirogermanium) in vitro. Cancer Res 42:2852–2856, 1982Google Scholar
- 12.Marsh JC: Bone marrow colony-forming cell sensitivity to carminomycin, marcellomycin and spirogermanium. Proc Am Assoc Cancer Res 22:241, 1981 (abstract)Google Scholar
- 13.Henry MC, Rosen E, Port CD, Levine BS: Toxicity of spirogermanium in mice and dogs after i.v. or im administration. Cancer Treat Rep 64:1207–1210, 1980Google Scholar
- 14.Byrne PJ, Schein PS, Maguire P, Hoth D, Smith F, Brown J, Wooley PV: Phase I clinical trial of spirogermanium. Proc Am Assoc Cancer Res 21:351, 1980 (abstract)Google Scholar
- 15.NCI Investigational Drugs. Pharmaceutical Data 1983 US Dept. of Health and Human Services. NIH Publication, No. 83241, Revised March 1983Google Scholar
- 16.Mattsson W: A phase I study of spirogermanium. Proc Am Assoc Cancer Res 21:194, 1980 (abstract)Google Scholar
- 17.Budman DR, Schulman P, Vinciguerra V, Degnan TJ: Phase I trial of spirogermanium given by infusion in a multiple dose schedule. Cancer Treat Rep 66:173–175, 1982Google Scholar
- 18.Gesme DH, Vogelzang NJ, Ryan M, Kennedy BJ: Phase I-II study of spirogermanium in advanced neoplastic disease. Proc Am Soc Clin Oncol 1:174, 1982 (abstract)Google Scholar
- 19.Asani JA, Legha SL, Burgess MA, Body GP: Phase I study of spirogermanium (SPG) given for five consecutive days per week. Proc Am Soc Clin One 1:16, 1982 (abstract)Google Scholar
- 20.Woolley P, Priego V, Luc V, Bollenbacher P, Schein P: A phase I trial of spirogermanium administered as a five day continuous infusion. Proc Am Assoc Cancer Res 24:136, 1983 (abstract)Google Scholar
- 21.Larsson H, Trope C, Mattsson W, Orbert B: Clinical pharmacokinetics of intravenously administered spiroger-manium. Proc Am Soc Clin Oncol 21:334, 1080 (abstract)Google Scholar
- 22.Mrema JEK, Slavik M, Davis J: Spirogermanium: A new drug with antimalarial activity against chloroquine-resistant plasmodium falciparum. Int J Clin Pharm Ther Tox 21:167–171, 1983Google Scholar
- 23.Trope C, Mattsson W, Gynning I, Johnson JE, Sigurdsson K, Orbert B: Phase II study of spirogermanium in advanced ovarian malignancy. Cancer Treat Rep 65:119–120, 1981Google Scholar
- 24.Brenner D, Forastiere A, Rosenschein N, Jones H, Dillon M, Grumbine F, Tipping S, Aisner J, Burnett L, Greco FA, Wiernik P: A Phase II study of spirogermanium in patients with advanced carcinoma of ovary and cervix. Proc Am Soc Clin Oncol 1:115, 1982 (abstract)Google Scholar
- 25.Espana P, Kaplan R, Robichaud K, Gustafson P, Wiernik P, Smith F, Woolley P, Schein P: Phase II study of spirogermanium in lymphoma. Proc Am Soc Clin Oncol 1:166, 1982 (abstract)Google Scholar
- 26.Falkson G, Falkson HC: Phase II trial of spirogermanium for treatment of advanced breast cancer. Cancer Treat Rep 67:189–190, 1983Google Scholar
- 27.Pinnamaneni K, Yap HY, Blumenschein GR, Legha SS, Bodey GP: Phase II study of 5 day continuous infusion of spirogermanium hydrochloride in metastatic breast carcinoma. Proc Am Assoc Cancer Res 24:151, 1983 (abstract).Google Scholar
- 28.Saiers JH, Slavik M: Evaluation of spirogermanium (NSC 192965) in adenocarcinoma of the prostate. Phase II. Southwest Oncology Group Protocol SWOG 8217.Google Scholar
- 29.Rieckmann KH, Sax LJ, Campbell GH, Mrema JE: Drug sensitivity of Plasmodium falciparum. An in vitro microtechnique. Lancet 1:22–23, 1978Google Scholar