A review of the investigational oncolytic agent hexamethylmelamine (HMM) is presented. HMM probably acts as an antimetabolite. The value of HMM lies in its relatively mild hematologic toxicity, its ability to increase response and survival rates in combination, and in its response in patients refractory to standard chemotherapy. The greatest response is in advanced ovarian cancer: Alone (overall response, 28–42 percent) and in combination with cyclophosphamide, mediotrexate, and 5-fluorouracil (overall response, 76–79 percent). Lung cancer has shown response to HMM, with best activity exhibited in small cell carcinoma (20–28 percent). HMM alone has demonstrated activity (overall response, 39 percent) in Hodgkin's and non-Hodgkin's lymphomas, a rate equal to that of bleomycin, and without cross resistance to this agent. Its value in breast cancer is questionable. The average tolerated dose is 8 mg/kg/d. Major dose-limiting toxicities are gastrointestinal, although hematopoietic depression, peripheral neuropathies, and central nervous system disorders also occur. Pentamethylmelamine, a water soluble metabolite, is die potentially marketable form of the drug.
SilverbergE.Cancer statistics, 1980. CA. Cancer Journal for Clinicians1980; 30 (1): 23–38.
2.
CalabreskiPParksRE, Alkylating agents, antimetabolites, hormones, and other antiproliferative agents. In: GoodmanLSGilmanA, eds. The pharmacologic basis of therapeutics. New York: Macmillan, 1975: 1254.
3.
LeghaSSSlavikMLivingstonKBCarterSK, Hexamethylmelamine, NSC-13875, Clinical Brochure.National Cancer Institute, 1974.
4.
WorzallaJFRamirezGBryanGT, N-demethylation of the antineoplastic agent hexamethylmelamine by rats and man. Cancer Res1973; 33: 2810–5.
5.
StolinskyDCBatemanJR, Further experience with hexamethylmelamine in the treatment of carcinoma of the lung. Cancer Chemother Rep1973; 57: 497–9.
6.
TakitaHDidolkarMS, Effect of hexamethylmelamine (NSC-13875) on small cell carcinoma of the lung. Cancer Chemother Rep1974; 58: 371–4.
7.
HeereIJDonnelyST, Antitumor activity of hexamethylmelamine and imidazole carboxamide. Proc Am Assoc Cancer Res1971; 12: 101.
8.
BryanGTWorzallaJFGorskeALRamirezG.Plasma levels and urinary excretion of hexamethylmelamine following oral administration to human subjects with cancer. Clin Pharmacol Ther1968; 9: 777–82.
9.
WorzallaJFKaimanBDJohnsonBMJohnsonROBryanGT, Biotransformations of a series of methylmelamine homologs of hexamethylmelamine. Proc Am Assoc Cancer Res1974; 15: 15.
10.
WorzallaJFKaimanBDJohnsonBMJohnsonROBryanGT, Metabolism of hexamethylmelamine-ring C in rats and man. Cancer Res1974; 34: 2669–74.
11.
LouisJLouisNBLinmanJWDonnellyWJIsaccsBLSchwartzSO, The clinical pharmacology of hexamethylmelamine: Phase I study. Clin Pharmacol Ther1967; 8: 55–64.
12.
WilsonWLde la GarzaJG. Phase I study of hexamethylmelamine (NSC-13875). Cancer Chemother Rep1965; 48: 49–52.
13.
BergevinPRTormeyDCBlomJ.Clinical evaluation of hexamethylmelamine (NSC-13875). Cancer Chemother Rep1973; 57: 51–9.
14.
WilsonWBiselHFColeDRochlinDRamirezGMaddenR.Prolonged low dose administration of hexamethylmelamine. Cancer1970; 25: 568–70.
15.
WilsonWLSchroederJMBiselHFMrazekRHummelRP, Phase II study of hexamethylmelamine (NSC-13875). Cancer1969; 23: 132–6.
16.
TakitaH.Hexamethylmelamine in inoperable bronchogenic carcinoma. NT State J Med1972; 72: 477–80.
17.
BlumRHLivingstonRBCarterSK, Hexamethylmelamine — A new drug with activity in solid tumors. Eur J Cancer1973; 9: 977–9.
18.
de la GarzaJGCarrDTBiseHF, Hexamethylmelamine (NSC-13875) in the treatment of primary cancer of the lung with metastases. Cancer1968; 22: 571–5.
19.
WamplerGLMelletteSJKupermincMRegelsonW.Hexamethylmelamine (NSC-13875) in the treatment of advanced cancer. Cancer Chemother Rep1972; 56: 505–14.
20.
SmithJ.Data presented at the symposium on ovarian carcinoma. Reston, Virginia, November, 1974.
21.
LeiteC.Hexamethylmelamine (HEX) with or without pyridoxine (Pyr) in refractory breast cancer. Proc Am Assoc Cancer Res1978; 19: 392.
22.
Hexamethylmelamine annual report to the FDA. Sponsored by Investigational Drug Branch, National Cancer Institute, Bethesda, MD. January, 1979.
23.
BordenECLarsonPAnsfieldFJ, Hexamethylmelamine treatment of sarcomas and lymphomas. Med Pediatr Oncol1977; 3: 401–6.
24.
JohnsonBLFisherRIBenderRA, Hexamethylmelamine in alkylating agent-resistant ovarian carcinoma. Cancer.1978; 42: 2157–61.
25.
HuangMNTakitaHCataneHChenT Yee. Therapy of small cell carcinoma of the lung with hexamethylmelamine. Oncology1978; 35: 29–32.
26.
StolinskyDCBogdonDLSolomonJBatemanJR, Hexamethylmelamine alone and in combination with 5-imidazole-4-carboxamide in the treatment of advanced cancer. Cancer1972; 30: 654–9.
27.
WhartonJTRutledgeFSmithJPHersonJHodgeMP, Hexamethylmelamine: An evaluation of its role in the treatment of ovarian cancer. Am J Obstet Gynecol1979; 133: 833.
28.
RubinPBakemeierRF, Clinical oncology for medical students and physicians. A multidisciplinary approach. 5th ed.American Cancer Society, 1978: Chapters 1,8,9,12.
29.
BonomiPMorrinBWilbanksGSlaytonR.Phase II trial of hexamethylmelamine (HMM) in ovarian carcinoma after alkylating agent failure. Proc Am Assoc Cancer Res1978; 19: 335.
30.
KardinalCGLuceJK, Evaluation of a hexamethylmelamine and 5-fluorouracil combination in the treatment of advanced ovarian cancer. Cancer Treat Rep1977; 61: 1691–3.
31.
DelgadoGScheinPMacDonaldJTulholskiHHaidakD.L-Pam vs. cyclophosphamide, hexamethylmelamine, and 5-fluorouracil (CHF) for advanced ovarian cancer. Proc Am Assoc Cancer Res1979; C-595: 434.
32.
YoungRCChabnerBAHubbardSP, Advanced ovarian adenocarcinoma: Melphalan (PAM) vs. combination chemotherapy (Hexa-CAF). Proc Am Assoc Cancer Res1978; 19: 393.
33.
YoungRCChabnerBAHubbardSP, Advanced ovarian adenocarcinoma: A prospective clinical trial of melphalan versus combination chemotherapy. N Engl J Med1978; 299: 1261–6.
34.
SmythJF, Characterization and treatment of human tumors. In: DavisWHarrapKR, eds. Advances in tumour prevention, detection and characterization. Amsterdam: Excerpta Medica, 1978: 332.
35.
OzolsRFGarvinAJCostaJSimonRMYoungRC, Histologic grade in advanced ovarian cancer. Cancer Treat Rep1979; 63: 255–63.
36.
GrecoTRichardsonRLHandeKR, Brief intensive chemotherapy and second look laparotomy in ovarian carcinoma. Proc Am Assoc Cancer Res1979; 20: 427.
37.
GreenwaldEVoglSEKaplaBHWollnerD.Hexamethylmelamine (H) and diaminedichloroplatinum (D) alone or with adriamycin (A) in patients with advanced ovarian cancer resistant to alkylating agents. Proc Am Assoc Cancer Res1978; 19: 327.
38.
BrowerMSColemanMChiarieriDRPasmantierMWSilverRT, Combination chemotherapy of ovarian carcinoma. Proc Am Assoc Cancer Res1979; 20: 186.
39.
KaneRHarveyHAndrewsT, Phase II trial of cyclophosphamide, hexamethylmelamine, adriamycin, and cisdichlorodiammineplatinum (II) combination chemotherapy in advanced ovarian carcinoma. Cancer Treat Rep1979; 63: 307–9.
40.
BrucknerHWWallachRCKabakowBGreenspanEMGusbergSBHollandJF, Cis-platinum (DDP) for combination chemotherapy of ovarian carcinoma: Improved response rates and survival. Proc Am Assoc Cancer Res1978; 19: 373.
41.
VoglSEKaplanBHMoukhtarMBerenzweigM.The CHAD and HAD regimens in advanced ovarian cancer: Combination chemotherapy including cyclophosphamide, hexamethylmelamine, adriamycin, and cis-dichlorodiammineplati-num (II). Cancer Treat Rep1979; 63: 311–7.
42.
AlbertsDSHilgersRDMoonTEMartimbeauPWRivkinS.Combination chemotherapy for alkylator resistant ovarian carcinoma. A preliminary report of a Southwest Oncology Group trial. Cancer Treat Rep1979; 63: 301–5.
43.
LeghaSSSlavikMCarterSK, Hexamethylmelamine, an evaluation of its role in the therapy of cancer. Cancer1976; 38: 27–35.
44.
GrecoFARichardsonRLSchulmanSFStroupSOldhamRK, Treatment of oat cell carcinoma of the lung: Complete remissions, acceptable complications, and improved survival. Br Med J1978; 2: 10–11.
45.
SchultzMJArmentroutSASlaterLMBatemanJR, Adriamycin/hexamethylmelamine vs. CCNU, vincristine, Cytoxan, and bleomycin in advanced oat cell, epidermoid, and anaplastic (NOS) lung cancer. Proc Am Assoc Cancer Res1979; 20: 427.
46.
GrecoFARichardsonRLSnellJDStroupSLOldhamRK, Small cell lung cancer. Complete remission and improved survival. Am J Med1979; 66: 625–30.
47.
MintzUBitranJDCookseyJADesserRKDemeesterTRGolombHM, Hexamethylmelamine, bleomycin, and CCNU chemotherapy for patients with squamous cell carcinoma, large cell carcinoma, and adenocarcinoma of the lung unresponsive to cyclophosphamide, adriamycin, methotrexate, and procarbazine. Cancer Treat Rep1978; 62: 567–9.
48.
KraussSTornyosK.Hexamethylmelamine (HMM) and cis-platinum diamminedichloride (DDP) in the treatment of non-oat cell lung cancer: A pilot study of the Southwestern Cancer Study Group. Cancer Treat Rep1979; 63: 391–3.
49.
KraussSTornyosKDeSimoneP, Cis-dichlorodi-ammineplatinum and hexamethylmelamine in the treatment of non-oat cell lung cancer. Proc Am Assoc Cancer Res1977; 18: 33.
50.
RegelsonWWamplerGSpremulliE.Chemotherapy of mesothelioma. Proc AmSoc Clin Oncol1977; 18: 299.
51.
BennettJMLenhardREEzdinliEJohnsonGJCar-BonePPPocockSJ, Chemotherapy of non-Hodgkins lymphomas: Eastern Cooperative Oncology Group experience. Cancer Treat Rep1977; 61: 1079–83.
52.
DenfrioJMVogelCL, Phase II study of hexamethylmelamine in women with advanced breast cancer refractory to standard cytotoxic therapy. Cancer Treat Rep1978; 62: 173–5.
53.
FabianCJRasmussenSStephensRSmithAHFBalcerzakSTranumB.Phase II evaluation of hexamethylmelamine in advanced breast cancer. A Southwest Oncology Group study. Cancer Treat Rep1979; 63: 1359–62.
54.
LongacreDDonavanMPaladineWCunninghamTSponzoR.Hexamethylmelamine, vincristine, and methotrexate chemotherapy in advanced neoplasms. Cancer Treat Rep1977; 61: 919–22.
55.
JarowskiCIPasmantierMColemanMSilverRT, Hexamethylmelamine, vinblastine, and mitomycin in the treatment of refractory adenocarcinoma of the breast. Proc Am Assoc Cancer Res1978; 19: 199.
56.
LawsonDHMooreMRSmalleyRV, An evaluation of hexamethylmelamine, cis-diamminedichloroplatinum and mitomycin-C in advanced breast cancer. Proc Am Assoc Cancer Res1979; 20: 369.
57.
Gad-El-MawlaNHamsaRChevlenEZieglerJ.Phase II chemotherapy trials in cancer of the bilharzial bladder. Proc Am Assoc Cancer Res1978; 19: 393.
58.
MawlaNM Gad-ElMuggiaFMHamzaMR, Chemotherapeutic management of carcinoma of the bilharzial bladder: A phase II trial with hexamethylmelamine and VM-26. Cancer Treat Rep1978; 62: 993–6.
59.
Clinical brochure—Pentamethylmelamine (NSC-118742). Investigational Drug Branch, National Cancer Institute, Bethesda, MD. June, 1978.
60.
HamlinRLPipersFSNguyenKMihalkoPFolkRM, Acute cardiovascular effects of pentamethylmelamine following continuous intravascular infusion to anesthetized beaglehounds. Toxicology Progam Office Battelle — Columbus; McLean, VA.
61.
AmesMMPowisGKovachJSEaganRT, Disposition and metabolism of pentamethylmelamine and hexamethylmelamine in rabbits and humans. Cancer Res1979; 39: 5016–21.
