Mitomycin C: a clinical update.

Mitomycin C was reviewed in this journal 25 years ago and an update of its clinical usefulness is appropriate. The current review is based on representative publications covering clinical trials performed throughout the world. Single agent activity in each of the major neoplastic diseases has been reassessed when possible and the most important combinations evaluated. It is concluded that mitomycin C has a definite place in the treatment of localized bladder cancer, is active, but needs to be redefined, in the context of newer regimens for breast, head and neck, and non-small cell lung cancers, is active in, but is being displaced by, other drugs in cervical, gastric and pancreatic cancers, and is probably no longer of therapeutic value in colon cancer. It is also recognized that as many newer treatments have clinical success, the therapeutic role of mitomycin C will require continuing re-investigation.

Experimental tumor inhibitory and toxic properties of the mitomycin A analogue 7-(2-hydroxyethoxy) mitosane (BMY-25551).

BMY-25551, 7-(2-hydroxyethoxy)mitosane, was selected from a series of mitomycin A (MMA) analogues for more detailed study. As with other members of this class, it was shown to be 8 to 20 times more potent than mitomycin C (MMC) in cytotoxicity to murine and human tumor cell lines in vitro, in causing DNA cross links in vitro, and in dose levels for tumor inhibition in vivo. BMY-25551 appeared to be more effective in tumor inhibition than MMC against P388 leukemia and B16 melanoma in mice and comparable to MMC against L1210 leukemia and Madison 109 lung carcinoma. BMY-25551 was also comparable to MMC in hematologic depression in mice. Factors affecting its possible utility in humans are discussed.

Phase I trial of FK973: description of a delayed vascular leak syndrome.

FK973 is a novel, substituted dihydrobenzoxazine structurally similar to mitomycin. FK973 lacks cross-resistance with mitomycin, doxorubicin, and vincristine in murine tumor models. A phase I study of FK973 was initiated using a 30-minute infusion repeated every 4 weeks. Of 17 patients enrolled on the study, a minimum of three patients were entered at each dose level: 7, 14, 21, 30, and 45 mg/m2. The dose-limiting toxicity was a vascular leak syndrome (VLS) characterized by pericardial and pleural effusions, ascites, and subcutaneous edema. These conditions were observed in two patients treated with a dose of 30 mg/m2 and in four who received 45 mg/m2. VLS was observed 2 weeks after the third dose of 30 mg/m2 and one week after the second dose of 45 mg/m2. Of nine patients treated with a cumulative dose greater than 60 mg/m2, five experienced this toxic reaction. Reversible drug-related pneumonitis was noted in one patient after the third course of 30 mg/m2. Moderate nausea and vomiting were initially observed at a dose of 14 mg/m2 and alopecia at 30 mg/m2. Grade 3-4 granulocytopenia was observed in two patients treated with 45 mg/m2. Extensive myocardial degeneration was observed at autopsy in a patient who had received three courses of 30 mg/m2. One patient with metastatic colon carcinoma and another with metastatic pancreatic carcinoma experienced partial clinical responses. Although the drug's clinical activity appears promising, additional investigation is needed into the mechanism of toxicity prior to further clinical development.

Antitumor and DNA-binding properties of a group of oligomeric complexes of Pt(II) and Pt(IV).

The antitumor and DNA-binding properties of a group of oligomeric platinum(II) and platinum(IV) complexes are described. The compounds, having the stoichiometry [cis-PtII(X)2(mu-OH)]2(NO3)2, where X is NH3, NH2CH2CH3, and NH2CH(CH3)2, were found to be inactive or only weakly active against L-1210 leukemia. In vitro studies involving PM2-DNA show that these compounds bind to and unwind closed circular DNA in a manner similar to cis-PtII-(NH3)2Cl2. The Pt(IV) complexes produced by hydrogen peroxide oxidation of the Pt(II) dimers are inactive as antitumor agents and are incapable of unwinding PM2-DNA. The cyclotrimer [cis-PtII(RR-DACH)(mu-OH)]3(NO3)3, where RR-DACH is (R,R)-1,2 diaminocyclohexane, exhibits potent antitumor activity against L-1210 leukemia and modest activities with B-16 and M5076 tumor lines. This compound platinates DNA, causing DNA unwinding and mobility shifts.

Experimental antitumor activity of BMY-28175 a new fermentation derived antitumor agent.

BMY-28175 is a novel antitumor antibiotic produced in fermentation by Actinomadura verrucosospora. The cytotoxic effects of BMY-28175 were determined using murine and human tumor cell lines in vitro. Following 72 hour exposure, the drug had IC50 values 1.5 to 13.5 ng/ml in a microtiter assay. BMY-28175 was evaluated for antitumor activity against several experimental murine and human tumor models. The drug administered ip was active against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma, M109 lung carcinoma, C26 colon carcinoma, M5076 sarcoma and Lewis lung carcinoma. In addition, BMY-28175 administered iv was active against iv implanted P388 and L1210 leukemias. BMY-28175 was active against sc implanted B16 melanoma (increased lifespan and/or inhibition of primary tumor growth) in about 60% of the tests. The growth of sc implanted M109 was inhibited by BMY-28175 in a single experiment. BMY-28175 was also active against the MX-1 human mammary xenograft implanted in the subrenal capsule of nude mice. The optimal dose for BMY-28175 in these various studies ranged from 0.16 micrograms/kg per injection with consecutive daily (qd1-9) administration, to 51.2 micrograms/kg with single dose administration. The results of these studies indicate that BMY-28175 is one of the most potent antitumor agents yet observed, with a broad spectrum of activity against tumors of murine and human origin and activity against tumors located distal to the site of drug administration.

Antitumor activity and toxicity in animals of N-7[2-(4-nitrophenyldithio) ethyl] mitomycin C (BMY-25067).

BMY-25067, N-7[2-(4-nitrophenyldithio)-ethyl] mitomycin C was selected from a number of disulfide derivatives of the highly active compound RR150, N-7(thioethyl) mitomycin C for further study. BMY-25067 had tumor inhibitory effects equivalent to mitomycin C (MMC) against ascitic P388 and L1210 leukemias and M109 lung carcinoma in mice with i.p. treatment. However, it demonstrated superior activity against B16 melanoma with a high percentage of cures when both tumors and drug were given i.p. Additionally, in separate tests against B16 melanoma implanted s.c. with treatment i.v., BMY-25067 was also consistently superior to MMC. This activity was observed when therapy was initiated either one day post-tumor implant or delayed until the ninth day post-tumor implant. Slight activity was seen against a line of L1210 partially resistant to MMC and none against a line of P388 completely resistant to MMC. Against s.c. M109, BMY-25067 inhibited tumor growth but did not prolong survival with the treatment schedule used. At their respective maximum non-lethal doses in mice, BMY-25067 was less neutropenic than MMC. This was confirmed in ferrets which were also examined for the compound's effects on platelets. BMY-25067 appeared to have much less effect on platelets than MMC; the nadir for BMY-25067 was 3.8 x 10(5) platelets/cmm compared to 7 x 10(4) platelets/cmm for MMC when the drugs were compared at a dose ratio of 2:1, BMY-25067:MMC (determined to represent their relative potencies). This initial evidence of superior antitumor effectiveness particularly to a solid tumor separated from site of treatment and reduced hematologic toxicity suggest that BMY-25067 may be a worthwhile candidate for clinical trial.

AT2433-A1, AT2433-A2, AT2433-B1, and AT2433-B2 novel antitumor antibiotic compounds produced by Actinomadura melliaura. Taxonomy, fermentation, isolation and biological properties.

Compounds AT2433-A1 (A1), AT2433-A2 (A2), AT2433-B1 (B1), and AT2433-B2 (B2) were isolated from the cultured broth of Actinomadura melliaura sp. nov. (SCC 1655). Structurally these materials are closely related to rebeccamycin (1), an indolocarbazole antitumor antibiotic. A1, A2, B1, and B2 were active against Staphylococcus aureus A9537, Streptococcus faecalis A20688, Streptococcus faecium (ATCC 9790), Micrococcus lutea (ATCC 9341), Bacillus subtilis (ATCC 6633). A1 and B1 were active against P388 leukemia in mice.

Structure-activity comparison of mitomycin C and mitomycin A analogues (review).

Over 600 analogues of mitomycin C (MMC) have been made in the past and more recently a number of Mitomycin A (MMA) derivatives have been prepared. Since many of the MMA type had the same organic side chain at the 7-position as previously prepared MMC analogues it was of interest to see if the biological effects of MMCs could predict for those of MMAs. Using the P388 leukemia model it was possible to compare the activity of 27 matched pairs and the potency of 24 pairs. It was found that antitumor effects did not correlate but that MMAs were significantly more potent than MMCs. These findings were duplicated in tests of 7 pairs against subcutaneously implanted B16 melanoma. We conclude that any MMA derivative would have a high likelihood of being more potent than its MMC equivalent but that its antitumor effects must be independently determined since they cannot be predicted from the results with MMC analogs.

Experimental antitumor activity of BMY-28090, a new antitumor antibiotic.

BMY-28090 is a novel actinomycete fermentation derived antitumor agent. The cytotoxic effect of BMY-28090 was evaluated in two murine and eight human tumor cell lines in vitro. Following 72-hour exposures, BMY-28090 was cytotoxic for all of these cell lines with IC50 values of less than 0.02 to 3.25 micrograms/ml. BMY-28090 was evaluated for in vivo antitumor activity in a variety of experimental murine tumor and human tumor xenograft models. Initial testing against the murine tumor models was performed using BMY-28090 as the water insoluble free base whereas subsequent antitumor tests were performed using water soluble lactate or succinate salts. BMY-28090 administered ip demonstrated good, reproducible antitumor activity against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma and M5076 sarcoma. The water soluble preparations of BMY-28090 were active iv against sc implanted B16 melanoma and M5076 sarcoma as well as subrenal capsule (src) M5076 sarcoma; activity against src implanted B16 was marginal. BMY-28090 lactate was also evaluated for activity against src implanted MX-1 human mammary tumor xenografts in nude mice and the HCT116 human colon tumor xenografts in immune-suppressed BDF1 mice. At maximum tolerated doses administered ip, BMY-28090 was active against the MX-1 xenograft in two of three tests, causing greater than 90% inhibition of tumor growth. BMY-28090 administered iv at maximally tolerated doses had marginal activity against the HCT116 xenografts, producing 61% and 68% inhibition of tumor growth in two tests. The results of these studies demonstrated that BMY-28090 has a broad spectrum of in vitro cytotoxicity against both murine and human tumor cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac, renal, and pulmonary toxicity of several mitomycin derivatives in rats.

The potential cardiotoxicity, nephrotoxicity, and pulmonary toxicity of several mitomycin (MMC) derivatives, BMY-25067 (N-7-[2-(4-nitrophenyldithio)ethyl]MMC), BMY-26107 (N-7-[2-(4-aminophenyldithio)ethyl]MMC), BMY-26605 (N-7 acetyl-MMC), BMY-25690 (7-N-(dimethylaminomethylene)-10-[1-morpholinomethyleneamino)carbo nyl- oxy]MMC), BMY-26646 (N-7-[2-(4-fluorophenyldithio)ethyl]MCC), and BMY-25551 (7-(2-hydroxyethyl)mitosane), were evaluated in rats. Groups of 10 male Sprague-Dawley rats were given single intravenous doses of the test compounds and were then observed for 10 weeks. Doses represented 67 and 33% of the respective mouse LD10 (corrected for body size on a mg/m2 basis) of each test compound. BMY-25282 (7-N-(dimethylaminomethylene)MMC), a mitomycin derivative that produces cardiac, renal, and arterial lesions, was used as a reference drug. Hematologic and blood chemical parameters were monitored at 3 days and at 3, 6, and 10 weeks after drug administration. Heart, kidney, and lung were examined histopathologically. Drug-related cardiac changes with late onset were seen histopathologically in rats treated with BMY-26605, BMY-25282, BMY-25551, and BMY-25690 (in order of decreasing severity). Drug-related renal changes, consisting of tubular degeneration and glomerulopathy, were seen in rats treated with BMY-25690, BMY-26107, BMY-25282, BMY-25551, BMY-26605, and BMY-25067 (in order of decreasing severity). Pulmonary arterial lesions were noted inconsistently in rats treated with BMY-26605, BMY-25282, and BMY-25551. Neither cardiac, renal, nor pulmonary changes were seen in rats administered BMY-26646, and only minor drug-related renal changes were seen in rats treated with BMY-25067.

Preparation and antitumor activity of additional mitomycin A analogues.

On the basis of qualitative structure-activity relationships developed in the preceding article, a series of 32 new mitomycin A analogues were prepared and tested in antitumor screens. Seven of them gave greater prolongation of life (ILS) than mitomycin C in the mouse P388 leukemia assay. They included examples with 7-O substituents such as cyclic ethers and nitrogen heterocycles. A Hansch analysis was attempted with log P and MR as the independent variables, but no statistically significant correlation could be made. Seven compounds, chosen mainly for their good potency (MED), were tested in the subcutaneous B16 melanoma assay in mice and four of them showed greater ILS than mitomycin C.

Production and biological activity of rebeccamycin, a novel antitumor agent.

An actinomycete, strain C-38,383, was selected in a screening program for the isolation of novel antitumor agents. A yellow crystalline product, named rebeccamycin, was isolated from the mycelium and was found to have activity against P388 leukemia, L1210 leukemia and B16 melanoma implanted in mice. Rebeccamycin inhibits the growth of human lung adenocarcinoma cells (A549) and produces single-strand breaks in the DNA of these cells. No DNA-protein cross-links were detected. A related antibiotic, staurosporine, is produced by Streptomyces staurosporeus and Streptomyces actuosus. Strain C-38,383 was found to resemble closely strains of Nocardia aerocolonigenes recently renamed Saccharothrix aerocolonigenes. A strain selection isolate without aerial mycelium, C-38,383-RK-1, failed to produce rebeccamycin while a strain with aerial mycelium, C-38,383-RK-2, was found to be a suitable strain for production. A description of the producing strain is presented and its taxonomic position is reviewed. A fermentor containing 37 liters of production medium gave a rebeccamycin yield of 663 mg/liter after 204 hours of incubation with strain C-38,383-RK-2.

Preparation and antitumor activity of new mitomycin A analogues.

A series of 26 mitomycin A analogues including 23 new ones was prepared by a variety of methods. The most useful methods were alkoxide exchange on mitomycin A and treatment of 7-hydroxymitosane with 3-substituted 1-phenyltriazenes. Many of the new analogues were superior to mitomycin C in the P388 leukemia assay and the more stringent subcutaneous B16 melanoma assay both in mice. Four of them gave long-term survivors in the latter assay. Quantitative correlations between log P and antitumor activity were not possible, but some guidelines for future analogue development are proposed.

In vivo characterization of P388 leukemia resistant to mitomycin C.

A line of P388 leukemia resistant to mitomycin C (MMC) was successfully developed in vivo by treating mice bearing parental P388 (P388/0) with MMC followed by serial passage of the surviving leukemic cells. From this P388/MMC line, a subline was derived by not treating the passage mice with MMC (P388/MMC-NP); resistance to MMC was stable for as many as 56 weeks of transplantation. The chemosensitivities of each P388 line to assorted anticancer drugs were compared in vivo. Both P388/MMC and P388/MMC-NP had similar patterns of drug cross-resistance and collateral sensitivity. With respect to alkylating agents (e.g. cyclophosphamide, Platinol and chlorambucil), there was generally a partial degree of cross-resistance, sometimes only detectable at suboptimal dose levels. With respect to DNA binders or intercalators (e.g. actinomycin D, luzopeptin A, amsacrine, doxorubicin), the extent of cross-resistance varied from none (dihydoxyanthraquinone) to marked (doxorubicin). Antimitotic inhibitors (vinblastine and vincristine) were completely cross-resistant, as were some miscellaneous natural agents (rebeccamycin, VP-16, sesbanimide, and elsamicin, a chartreusin analog). Antimetabolites (e.g. methotrexate and 6-thioguanine) showed no cross-resistance and even demonstrated some occasional evidence of collateral effectiveness.

Preparation and antitumor activity of 7-substituted 1,2-aziridinomitosenes.

7-Methoxy-1,2-aziridinomitosenes were prepared from mitomycin A and its N-methyl homologue by catalytic reduction followed by air oxidation. Treatment of these products with amines, including ammonia, ethylenimine, 2-methylethylenimine, propargylamine, and furfurylamine gave the corresponding 7-(substituted amino) derivatives. Screening of these compounds against P-388 leukemia in mice revealed some good activities. The more easily reduced compounds gave prolongation of life span comparable to that of mitomycin C, but their optimal doses were higher. Among these compounds, a methyl group on the aziridine nitrogen increased potency. The 7-amino derivatives, which were difficult to reduce to hydroquinones, were essentially inactive. The aziridinomitosenes were subjected to a Hansch-type analysis, but no statistically significant correlation was found.

Mitomycin C analogues with increased metal complexing ability.

Twenty-three new mitomycin C analogues designed to have increased metal complexing ability were synthesized and tested against P388 leukemia in mice. Their ability to complex Cu(II) was revealed by the shifts in their UV absorption spectra caused by this metal. One analogue was clearly more active than mitomycin C in the antitumor assay and two others had good activity. Correlation between antitumor activity and Cu(II) complexing ability was ambiguous. The most active compounds were either not complexers or they were complexers limited to the 2-(2-pyridyl)alkyl type substituent on N7. A variety of amino acid substituents on N7 showed only weak antitumor activity.