Cancer mitomycin

This approach has been used primarily in Japan to treat patients with malignant, inoperable hepatic cancer. Mitomycin C contained in albumin microspheres was administered to patients (122) by percutaneous intraarterial catheterization. Tumor reduction was seen in over 68% of the cases. By contrast, the control group, receiving infusion therapy, had a poorer response. Survival times were also greater for patients receiving the microspheres. 

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Aziridines occur naturally in the form of mitomycins (Table 3), which have antibiotic activity (1,449). Mytomycin C is used clinically as one of the most effective agents in the chemotherapy of cancer (450). 

There were some early clinical studies of carzinophilin, both alone [131,132] and in combination with mitomycin C, in humans [133]. Despite showing promising reduction in the number of cancer cells, there were significant toxic side effects and clinical application has not been pursued any further. 

Wientjes MG, Badalament RA, An JL. Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer. Cancer Chemother Pharmacol 1993,32(4) 255-62. 

The continuing interest in bioreductive alkylation is largely due to the clinical success of mitomycin C and the low reduction potentials observed in many tumors.9 The low reduction potentials favor the quinone to hydroquinone conversion necessary for bioreductive alkylation. Hypoxia due to low blood flow3 and/or the unusually high expression of the quinone two-electron reducing enzyme DT-diaphorase in some histological cancer types10-14 contribute to the tumor s tendency to reduce quinones. 

Cummings, J. The role of reductive enzymes in cancer cell resistance to mitomycin C. Drug Resist. Update 2000, 3, 143-148. 

Mitomycin C is an alkylating agent that forms cross-links with DNA to inhibit DNA and RNA synthesis. The pharmacokinetics of mitomycin C are best described by a two-compartment model, with an a half-life of 8 minutes and a terminal half-life of 48 minutes.31 Liver metabolism is the primary route of elimination. Mitomycin C has shown clinical activity in the treatment of anal, bladder, cervix, gallbladder, esophageal, and stomach cancer. Side effects consist of myelosuppression and mucositis, and it is a vesicant. 

In a somewhat similar scheme, Noguchi et al. (1992) prepared a carboxylate spacer arm by reacting 6-bromohexanoic acid with a dextran polymer. The carboxylate then was aminated with ethylene diamine to form an amine-terminal spacer (Figure 25.15). This dextran derivative finally was reacted with N-Succinimidyl 3-(2-pyridyldithio)propionate (SPDP) (Chapter 5, Section 1.1) to create the desired sulfhydryl-reactive polymer (Section 2.4, this chapter). The SPDP-activated polymer then could be used to prepare an immunoconjugate composed of an antibody against human colon cancer conjugated with the drug mitomycin-C. 

Noguchi, A., Takahashi, T., Yamaguchi, T., Kitamura, K., Takakura, Y., Hashida, M., and Sezaki, H. (1992) Preparation and properties of the immunoconjugate composed of anti-human colon cancer monoclonal antibody and mitomycin C—Dextran conjugate. Bioconjugate Chem. 3, 132-137. 

The importance of superoxide-mediated damage to cancer cells was also demonstrated in the experiments with overexpressed mitochondrial MnSOD. Hirose et al. [186] showed that the overexpression of mitochondrial MnSOD enhanced the survival of human melanoma cells exposed to cytokines IL-1 and TNF-a, anticancer antibiotics doxorubicin and mitomycin C, and y-irradiation. Similarly, Motoori et al. [187] found that overexpression of MnSOD reduced the levels of reactive oxygen species in mitochondria, the intracellular production of 4-hydroxy-2-nonenal, and prevented radiation-induced cell death in human hepatocellular... 

Although reduction of quinones is usually a detoxication pathway, there are examples such as mitomycin C in which the hydroquinone is more toxic than the quinone as shown in Figure 5.12 and this may increase the susceptibility of cancers that express high levels of NQO. In this case, the reduction of the quinone leads to the loss of methanol, which is the first step in the activation of this anticancer agent (20). 

Chemotherapeutic agents that have significant cancer response when combined with hyperthermia (up to 43°C) include doxorubicin, melphalan, mitomycin C (MMC), mitoxantrone, gemcitabine, etoposide, and especially the platinum-based agents carboplatin and oxaliplatin (Mohamed et al., 2003 Sugarbaker et al., 2005). Agents that do not work well with hyperthermia include irinotecan, paclitaxel, docetaxel, 5-fluorouracil, and floxuridine (Mohamed et al., 2003 Sugarbaker et al., 2005). 

Keyes SR, Loomis R, DiGiovanna MP, Pritsos CA, Rockwell S, Sartorelli AC (1991) Cytotoxicity and DNA crosslinks produced by mitomycin analogs in aerobic and hypoxic EMT6 cells. Cancer Commun 3(10-11) 351-356... 

The mitomycins (331) have attracted much attention as a result of their interesting structure and especially because of their potent anti-cancer properties [102]. One approach to these materials is illustrated in Scheme 22 [103]. A key intermediate in the implementation of this plan is azocinone 333, a substance... 

Mitomycin C Lung cancer. Various disseminated refractory malignandes. Gastric cancer... 

Short term treatment with TPA sensitized human 2008 ovarian carcinoma cells to cis-platin. This sensitization disappeared completely by seven hours after treatment, indicating that not inhibition, but activation of PKC sensitizes 2008 cells to the antiproliferative activity of cis-platin (Isonishi et al., 1990). Pretreatment of HeLa cells with TPA or PdBu caused a 9-fold increase in cellular sensitivity to cis-platin and 2.5-fold to melphalan, but had now effect on the antiproliferative activity of bleomycin, adriamycin, vincristine, or mitomycin C. The sensitization of HeLa cells by TPA was associated with a 6-fold stimulation of PKC activation and a concentration- and time-dependent increase in cellular platinum content. (Basu et al. 1990). PKC activity was found to be decreased significantly in cis-platin-resistant human small cell lung H69/CP cancer cells compared to the drug-sensitive variant. A similar reduction in PKC activity was noted in ovarian carcinoma 2008 cells that were resistant to cis-platin. A modest decrease in PKC activity was also observed in etoposide-resistant H69 cells but not in taxol-resistant H69 cells or bleomycin-resistant human head and neck carcinoma A-253 cells (Basu et al., 1996), indicating that reduced PKC activity leads to decreased sensitivity in this system. 

Akinaga S, Nomura K, Gomi K, Okabe M (1993) Enhancement of antitumor activity of mitomycin C in vitro and in vivo by UCN-01, a selective inhibitor of protein kinase C. Cancer Chemother Pharmacol 32 183-189... 

Fitzsimmons SA, Workman P, Grever M, Pauli K, Camalier R, Lewis AD (1996) Reductase enzyme expression across the National Cancer Institute tumor cell line panel correlation with sensitivitry to mitomycin C and E09. J Natl Cancer Inst 88 259-269... 

Cummings B J, Keane TJ, O Sullivan B, et al. Epidermoid anal cancer treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. Int J Rad One Biol Phys 1991 21(5) 115-125. 

UKCCCR Epidermoid anal cancer results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Coordinating Committee on Cancer Research. Lancet 1996 348 1049-1054. 

UFT was studied in combination with radiation therapy in patients with locally advanced, inoperable gastric carcinoma. Tsukiyama et al. (66) evaluated combined modality therapy (CMT) consisting of UFT and mitomycin-C administered together with radiation therapy, and reported local control in 70% of patients with advanced inoperable gastric cancer. 

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