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The title compound, [1aS]-6-amino-1, 1a,2,4,7,8,8a,8b-octahydro-8a-hydroxy-1,5-dimethyl-4,7-dioxoazirino++ +[2',-3': 3,4]pyrrolo[1,2-a]indol-7-ylmethyl, is a mitomycin derivative, mitomycins being antitumor antibiotics. The O atoms of the quinone ring deviate significantly from the least-squares plane through the quinone ring.
A high molecular weight derivative of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D) has been synthesized and its biological and pharmacological properties investigated. MMC is released from MMC-D in vitro with a half-life of 24 h. After intraperitoneal injection of MMC-D, free MMC could be detected in plasma and urine of mouse for 5--8 h, while MMC administered as a free form was eliminated rapidly. After MMC-D, given to mice bearing Ehrlich ascites carcinoma or B16 melanoma there was a reduction in toxicitst that the high molecular weight MMC-dextran derivative is a kind of pro-drug which persists in the body giving a sustained release of free MMC thus significantly increasing the antitumour activity of the parent drug.
Carcinoma of unknown primary (CUP) site accounts for approximately 6.5% of all cancers. Optimal therapy for patients with CUP has not yet been delineated. The current study was undertaken to evaluate response, time to treatment failure and survival in patients with CUP treated with a combination regimen comprising mitomycin C, epirubicin and cisplatin (MEP) versus mitomycin C alone (MITOC). Eighty-four patients with CUP were randomised to receive either the combination (MEP) or MITOC. Both treatment arms were well matched for age, gender, performance status, dominant site and number of disease sites. Eighty of the above patients were evaluable. Twenty patients (50%) treated with MEP responded to treatment compared with 7 (17%) who received MITOC. Grade III-IV hemopoietic toxicity was documented in 2 patients treated with MEP and no patients treated with MITOC. A single patient treated with MEP developed grade I peripheral neuropathy. Median time to treatment failure was 4.5 months for patients receiving MEP as opposed to 2 months for those receiving MITOC (p = 0.05). Median survival was 9.4 months in patients treated with MEP compared to 5.4 months in those receiving MITOC (p = 0.05). This study indicates that the addition of cisplatin and epirubicin to MITOC results in a significant improvement in the response rate, time to treatment failure and survival in patients with adenocarcinoma of unknown primary site.
In the present comparative study, we examined an intra-arterial chemotherapy combined with PJ-203 in 60 patients with liver cancer metastasized from gastrointestinal cancer, using an intra-arterial chemotherapy alone as the control. Sixty patients who had been registered by telephone contact were allocated to groups either treated with the intra-arterial chemotherapy alone or with PJ-203 combined, 30 patients each. Mitomycin C was used as the anticancer drug and given at the dose of 8mg/m2 per time. The dose of PJ-203 was 600 +/- 300 mg as degradable starch microspheres. A significantly higher response rate (CR + PR/complete cases) of 54.5% (p = 0.021) was noted in the PJ-203 combined group, as compared to 20.0% for the control group. The 50% survival duration was 282 and 214 days for the PJ-203 combined group and control group, respectively, with no significant difference being noted between the two groups. Principal adverse reactions such as pain, gastrointestinal symptoms and fever were statistically more frequent (p < 0.01) in the PJ-203 combined group than in the control group. Among the abnormal laboratory values, the incidence of decreased leukocytes was significantly lower (p = 0.022) in the PJ-203 combined group than in the control group. One of the patients concomitantly treated with PJ-203 died of drug-induced hepatitis, which was probably attributed to mitomycin C. However, overall utility assessment was significantly better (p = 0.002) in the PJ-203 combined group.
The results of a comparative randomized study on intravesical chemoprophylaxis are presented. The study comprised 66 patients; one group of 29 patients received mitomycin C alone, while another group of 37 patients received mitomycin C and alternating BCG therapy. This latter treatment modality was found to achieve a slightly higher complete response rate and a much lower tumor progression rate. Although these results were not statistically significant (p > 0.05), they indicate that if the study were comprised of a larger series, the combined modality may be shown to achieve better results than the other modalities currently used.
A total of 60 patients with transitional cell carcinoma of the bladder G1-G2, pTa pT1 previously subjected to TUR, were randomised to receive Mitomycin-C (MMC) 30 mg for 12 months (A group) or Mitomycin-C 40 mg for 6 months (B group). The objective of this trial was to compare the prophylactic activity of MMC using two different dosages and treatments. All patients were evaluated with cystoscopy. Follow-up was of 24 months. The incidence of recurrence in the A group was 40% with a recurrence rate of 3.3. In the B group the incidence of recurrence was 27.6% with a recurrence rate of 2.2. One case of progression was present in the A group. The side effects were more frequent in the A group (37% vs 13.3%) and they were mainly due to chemocystitis. These data suggest that MMC 40 mg for 6 months appears to be superior to MMC 30 mg for 12 months in the prophylaxis of superficial bladder carcinoma.
Thirty-two patients with inoperable hepatic cancer underwent intra-arterial hepatic infusion using mitomycin C (MMC) and 5-fluorouracil (5-FU) or intra-arterial hepatic chemoembolization using heated albumin microspheres containing MMC with an average diameter 45 +/- 8 micron. Nineteen of the 32 patients received the MMC microsphere treatment and another 13 received the conventional infusion treatment, lasting for 3.4 months. The administered doses of MMC microspheres were 11.7 +/- 11.1 mg as MMC in the 12 with metastatic cancer and 6.9 +/- 2.1 mg as MMC in the 7 with hepatocellular cancer (HCC). On the contrary, the 13 patients who underwent conventional infusion had average doses of MMC 34.5 +/- 17.3 mg and of 5-FU 13.4 +/- 7.7 g, over 3.4 months. An objective tumor response was obtained in 13/19 (68.4%) under MMC microsphere chemoembolization, compared to 6/13 (46.2%) under the conventional infusion. The average level of CEA in the 12 with metastatic cancer, who underwent MMC microsphere therapy, dropped from 57.7 ng/ml to 16.5 ng/ml, while that in the 10 patients on conventional infusion dropped from 24.0 ng/ml to 17.4 ng/ml; that of alpha-fetoprotein dropped in all 7 with HCC on MMC microsphere chemoembolization, compared to a fall in 1/3 on conventional infusion. With the MMC microsphere treatment, 5 patients from colorectal cancer lived for 15.6 +/- 7.6 months, 2 are alive with a long life expectancy; and 7 patients from gastric or pancreatic cancer lived for only 9.3 +/- 3.3 months. In case of conventional infusion, 6 patients from colorectal cancer survived for 8.6 +/- 3.2 months; and 4 patients from gastric or gallbladder cancer survived for 6.0 +/- 1.0 months. The MMC microsphere treatment is superior at P = 0.059 in survival duration to the conventional infusion treatment. However, much the same survival occurred in 7 on MMC microsphere chemoembolization and 3 on continuous infusion.
Knowledge of the metabolism of the anticancer drug mitomycin C (MMC) is necessary in order to optimize the administration schemes of this drug. The present study concentrates on the metabolism of MMC in liver homogenates. Various mass spectrometric methods have been investigated for their usefulness in the metabolic studies on MMC by comparing the mass spectral data. Data from electron impact, direct probe chemical ionization, direct chemical ionization, field desorption and thermospray ionization have been obtained. One of the soft ionization methods, i.e. direct chemical ionization, has been applied to the detection of MMC in a spiked piglet liver sample. It appears to be necessary to enhance the selectivity of the method by using tandem mass spectrometry, owing to the high biological background.
The characteristics of liposomes and an oil-water emulsion containing either mitomycin C (MMC) or its lipophilic prodrugs were investigated. Prodrugs were incorporated into liposomes and oil droplets of an oil-water emulsion, and this incorporation was dependent on the lipid content of the liposomes and droplets. A good correlation was observed between the calculated lipid:water partition ratios and partition coefficients in chloroform:water. The prodrugs were rapidly distributed between the lipid and aqueous phases when they were injected into the dispersion medium of empty liposomes and an oil-water emulsion, or when the formulations incorporating prodrugs were diluted with water. Addition of prodrugs to liposomes containing perylene resulted in a decrease of fluorescence. Based on these findings, prodrugs were concluded to be incorporated into lipidic dispersion formulations based on their partitioning behavior. N1a-[(Nonyloxy)carbonyl]MMC (7) showed the highest incorporation into lipidic formulations, while prodrugs with moderate lipophilicities were rapidly released from lipid particles. Liposomes incorporating 7 maintained their multilamellar vesicular form as shown by electron microscopy and by examining their entrapping capacity for water soluble marker dyes. The release of prodrug 7 from both formulations was slow in a buffer solution, but considerable release and conversion to the parent drug were observed when rat plasma was added to the same system. These results suggest that the stability of MMC could be improved by incorporation into lipidic formulations and that a suitable release rate in vivo could be accomplished by use of a prodrug.
KW-2149, a new mitomycin C (MMC) derivative, inhibited the growth of murine P388 leukemia in vitro at 20-fold lower concentrations than those of MMC. KW-2149 was also effective in inhibiting the growth of MMC-resistant P388 (P388/MMC) cells. To elucidate these characteristics of KW-2149, its uptake and efflux were compared with those of MMC in MMC-sensitive and -resistant P388 cells. Both MMC and KW-2149 accumulated rapidly in P388 cells after incubation at the concentration of 0.47 and 0.024 microM, respectively, which were the IC50 values at 1-h exposure. Although this concentration of KW-2149 was 20 times lower than that of MMC, its intracellular concentration was little more than that of MMC, suggesting that KW-2149 accumulated in the cells quite efficiently. The accumulated KW-2149 in the cells after 1-h treatment remained for as long as 24 h after the incubation of the cells in drug-free medium, suggesting that most of the intracellular KW-2149 or MMC was bound to cellular components. The ratios of resistance of P388/MMC cells to MMC and KW-2149 were 34 and 8.8, respectively, at 1-h exposure, suggesting that P388/MMC cells were partially resistant to KW-2149 in vitro. P388/MMC cells also showed partial resistance to cisplatin, Adriamycin, m-AMSA, and etoposide. The accumulation of MMC in P388/MMC cells was lower than that in P388 cells, although the size of the former cells was almost equal to that of the latter. As a result, the amount of DNA-bound MMC was lower in P388/MMC cells than in P388 cells, suggesting its involvement in the mechanisms of MMC resistance in P388/MMC cells.
The mechanism of action of a new mitomycin C (MMC) derivative, KT6149, was studied in human leukemia HL-60 cells and in isolated phage and plasmid DNA, and its effects were compared with those of MMC. Cell growth was markedly inhibited by KT6149, with an IC50 of 2 x 10(-9) M, that for MMC being 2 x 10(-8) M. DNA synthesis of HL-60 cells as determined by incorporation of [3H]-thymidine was also inhibited by KT6149, with an IC50 of 2 x 10(-7) M as compared with 2 x 10(-6) M for MMC. RNA and protein synthesis were less markedly inhibited at low concentrations. Alkaline sucrose density-gradient centrifugation revealed a significant decrease in sedimentation velocity for cellular DNA of the cells after 1 h treatment with KT6149 at concentrations higher than 10(-7) M. In contrast, no such change was observed for DNA of cells treated with MMC, even at a concentration of 10(-5) M. In a cell-free system, analysis by agarose gel electrophoresis patterns showed that the drug induced a decrease in the amount of covalently closed circular DNA of phage PM2 and an increase in that of open circular DNA in the presence of dithiothreitol (DTT), whereas MMC did not cause any change in DNA subfraction amounts. Furthermore, the electrophoretic mobility of linearized pBR322 DNA in alkaline agarose gel was significantly decreased by KT6149 in the presence of DTT and FeSO4, no such change being observed in the case of MMC. The results clearly indicate that the inhibitory effects of KT6149 on the growth and DNA synthesis of HL-60 cells are more potent than those of MMC and that KT6149-induced DNA damage is due to single-strand scission and to cross-linking of DNA, suggesting a mode of activation different from that of MMC.
Observations were made on living neuroblasts (Nbs) of the grasshopper (Chortophaga viridifasciata) embryo during a 4-h recovery period following 1-h in vitro exposure to 10(-8), 10(-6), and 10(-4) M mitomycin C (MMC). None of these concentrations affected the duration of mid-mitosis (prometaphase, metaphase, anaphase), but one as low as 10(-8) M causes a small reduction in the rate at which Nbs move through the remainder of the cell cycle, primarily by retarding their progress through S. As the concentration is increased there is slower movement through S and also prophase (there are no true G1 and G2 periods in the rapidly dividing Nb: 4-h cell cycle at 38 degrees C). A significant proportion of the cells exposed to 10(-4) M are blocked for 1 or more h at very late prophase, i.e., just before nuclear membrane breakdown. In such retarded prophases the chromosomes resemble c-metaphase chromosomes even though the nuclear membrane remains intact. Mass spectrometry data revealed that one lot of the MMC used contained one or more impurities.
Anthramycin and mitomycin C (MC) are two DNA reactive drugs, which bind covalently to GC pairs producing different effects on DNA: anthramycin stiffening and MC distorsion. This paper describes experiments in which we have used anthramycin as a probe to sense quantitatively the effects on DNA of MC binding. Saturation binding experiments show that both anthramycin and MC partially inhibit the binding of the other drug to DNA (maximum inhibition by MC and anthramycin, 22.4% and 19.7%, respectively) but by a mechanism other than direct site exclusion. This suggests that MC binds in the major groove of DNA, since anthramycin is known to bind in the minor groove. An abrupt reduction in the binding of anthramycin to DNA-MC complexes occurs between MC binding ratios of 0.030 and 0.035, which parallels and probably results from sudden intensification of a MC-induced DNA conformational change occurring between these binding ratios. Dialysis measurements indicate that anthramycin is very possibly binding at sites distant from MC sites and suggest a clustering of closely bound MC chromophores resulting from possible cooperative binding. S1 nuclease digest experiments demonstrate an initial enhancement of nuclease activity in DNA-MC complexes, the magnitude of which correlates well with the reduction of anthramycin binding, relative to the degree of MC binding. The enhanced nuclease activity in these complexes indicates regions of exposed DNA or helix base distortion which is related to or is the result of conformational change.
A randomized controlled trial involving 13 institutions in Japan was conducted in order to compare the efficacy of tegafur plus mitomycin C (MMC) (Regimen A) and UFT (a combination of uracil and tegafur at a molar ratio of 4 to 1) plus MMC (Regimen B) for patients with advanced gastric cancer, who had not received any prior cancer chemotherapy. Regimen A (tegafur + MMC) consisted of 5 mg of MMC/m2/week given intravenously, and 500 mg of tegafur/m2/day given orally. Regimen B consisted of the same schedule of MMC and 375 mg of UFT/m2/day given orally. One hundred and eighty-six patients with primary gastric cancer were entered; 183 were eligible and 3 were ineligible for the study. A total of 169 were evaluable for efficacy of the treatment, including 90 patients with Regimen A and 79 with Regimen B. A response rate of 7.8% (7/90 cases) for Regimen A and one of 25.3% (20/79 cases) for Regimen B were obtained, indicating a significantly higher response rate for Regimen B according to the Criteria for Evaluating Efficacy of Chemotherapy/Radiation Therapy in the Treatment of Gastric Cancer (P = 0.004). Regarding side effects, no marked differences in either severity or incidence were observed between the two groups. The group assigned to Regimen B showed a significant survival advantage after adjustment for major prognostic factors using a proportional hazards model (P = 0.0398). Moreover, a close correlation of antitumor effect and survival duration was found when the above criteria were used.
The conjugate between N-succinyl-chitosan (Suc-chitosan) and mitomycin C (MMC), named Suc-chitosan-MMC, and that between carboxymethyl-chitin (CM-chitin) and MMC, named CM-chitin-MMC, were investigated in vivo. As for the intraperitoneal drug administration using rats, the order of the maximum blood concentration of MMC was unconjugated MMC > CM-chitin-MMC > Suc-chitosan-MMC. The plasma concentration of MMC for Suc-chitosan-MMC was maintained at an almost constant level over 24 h. Pharmacokinetic analysis of each plasma concentration indicated that for each conjugate, the in vitro drug release reported previously was useful for the approximate estimation of the in vivo regeneration of MMC. The chemotherapeutic effect of MMC and the conjugates was investigated using mice bearing L1210 leukemia or B16 melanoma. Concerning antitumor activity against L1210 leukemia, the conjugates exhibited a marked effect at higher doses, and their effect increased even in the dose range where the effect of MMC decreased. MMC and the conjugates exhibited a good growth-inhibitory effect against B16 melanoma. Complete inhibition of growth of B16 melanoma was observed at the dose of 10 mg eq MMC/kg for CM-chitin-MMC.
Treatment of EMT6 mouse mammary tumor cells with [3H]mitomycin C (MC) results in the formation of six major DNA adducts, as described earlier using an HPLC assay of 3H-labeled products of enzymatic hydrolysis of DNA isolated from MC-treated cells. Four of these adducts were identified as monofunctional and bifunctional guanine-N2 adducts in the minor groove of DNA. In order to establish relationships between individual types of MC-DNA adducts and biological responses it is necessary to identify all of the adducts formed in cells. To this end we have now identified a predominant, previously unknown adduct formed in MC-treated EMT6 cells as a derivative not of MC, but of 2,7-diaminomitosene (2,7-DAM), the major bioreductive metabolite of MC. Rigorous proof demonstrates that it is a DNA major groove, guanine-N7 adduct of 2,7-DAM, linked at C-10 to DNA. The adduct is relatively stable at ambient temperature, but is readily depurinated upon heating. Its isolation from MC-treated cells indicates that MC is reductively metabolized to 2,7-DAM, which then undergoes further reductive activation to alkylate DNA, along with the parent MC. Low MC:DNA ratios were identified as a critical factor promoting 2,7-DAM adduct formation in an in vitro model calf thymus DNA/ MC/reductase model system, as well as in MC-treated EMT6 cells. The 2,7-DAM-guanine-N7 DNA adduct appears to be relatively noncytotoxic, as indicated by the dramatically lower cytotoxicity of 2,7-DAM in comparison with MC in EMT6 cells. Like MC, 2,7-DAM exhibited slightly greater cytotoxicity to cells treated under hypoxic as compared to aerobic conditions. However, 2,7-DAM was markedly less cytotoxic than MC under both aerobic and hypoxic conditions. Thus, metabolic reduction of MC to 2,7-DAM represents a detoxification process. The differential effects of MC-DNA and 2,7-DAM-DNA adducts support the concept that specific structural features of the DNA damage may play a critical role in the cytotoxic response to a DNA-targeted chemotherapeutic agent.
The interaction of hyperthermia and mitomycin C (MMC) was studied in wild-type Chinese hamster ovary cells and in Chinese hamster ovary cells selected for resistance to MMC. Hyperthermic potentiation of MMC activity was maximal if heating was done simultaneously, or up to 3 h following MMC exposure. Heat enhanced the effect of MMC in both drug-sensitive and -resistant cells. Dose enhancement ratios increased from 1.3-2.0 at 42 degrees C to 2.6-3.8 at 43.5 degrees C and were similar for all cell lines. Cellular uptake of MMC was determined by high pressure liquid chromatography. MMC uptake was similar in the drug-sensitive and -resistant cell lines at 37 degrees C. Hyperthermia (43.5 degrees C) increased cellular uptake of MMC by 78 and 27% in MMC-sensitive and -resistant cell lines. MMC-resistant cells were more sensitive to heat alone at 42, 43, and 44 degrees C. The results suggest that tumor cells that have developed resistance to MMC might be treated effectively with MMC combined with heat to augment the response to MMC. Resistance to MMC may also render tumor cells more sensitive to hyperthermia.
BMY25282, a newly designed analogue of mitomycin C (MMC) with the substitution of an amidine group at position 7 of MMC, can circumvent MMC resistance in a series of human colonic carcinoma cells that were selected for resistance to MMC (J.K.V. Willson et al., Cancer Res., 45:5281-5286, 1985). In this study MMC resistance was found to be associated with an inability of the resistant cells to activate MMC. However, both the MMC-sensitive and -resistant cells were observed to metabolize BMY25282 extensively in vitro to a reactive species capable of alkylating 4-(p-nitrobenzyl)pyridine (a trapping agent for activated drug). The results of these studies suggested that the deficient cellular reductive activating mechanism was associated with MMC resistance and that analogue BMY25282 was able to overcome this deficiency in MMC-resistant cells by virtue of its enhanced activation.