Problems in cancer treatment

A major problem in treating patients with cancer is our inability to selectively destroy metastatic neoplastic cells. Surgery and radiotherapy are often effective in eradicating primary tumours. Increased awareness of cancer over the last two decades, both amongst the public and physicians, has resulted in the presentation of malignant disease at an earlier stage. Despite this, nearly 50% of patient's with common solid tumours have metastatic disease at the time of presentation. Screening programs and increased public awareness are unlikely to change this statistic significantly. Variations in the way in which physicians deal with the primary disease can have no effect on the survival of patients with metastases. This is exemplified in breast cancer where considerable controversy has been generated about the best way to use combinations of surgery and radiotherapy. The end results, however, remain constant with 40 % of patients dying within 5 years. The treatment of metastatic disease clearly requires systemic therapy. For this to be effective it must discriminate between malignant and non-malignant cells. Chemo- and endocrine therapy can often do this, but unfortunately neoplastic cells can rapidly devise mechanisms to resist therapy. Most hemotherapeutic regimes are empirical, with drug combinations designed to avoid additive toxicity.

The current treatment of metastatic disease for common solid tumours can be compared to the treatment of infectious diseases in the pre-antibiotic era of the 1930s. The differences between behavior of the malignant cell and its normal counterpart are so subtle that any drug which is capable of destroying malignant cells, will undoubtedly also have a significant effect on a large number of normal cells. This unwanted toxicity on the normal cells may require the cancer treatment to be stopped. For example an ovarian carcinoma may be treated by chlorambucil which is taken daily by mouth. Chlorambucil is effective in destroying proliferating cells but is particularly active against cells of the lymphoid series when given in doses large enough to be effective against the ovarian turmour. It may also cause a significant depression of the circulating white cell count and thus render the patient liable to infection and death due to septicemia. Such toxicities are limiting in employing drugs against certain malignant diseases. All drugs effective against cancer have considerable side-effects on normal tissue which may in themselves be extremely hazardous for the patient. It is for this reason that their use is restricted to physicians who are specially trained and experienced. One example of a dose-limiting toxicity is adriamycin, an antibiotic active against breast cancer. This causes complete hair loss and damage to the muscles of the heart. Another is in cis-dichlorodiaminoplatinum, a compound extremely valuable in the treatment of many cancers which cause renal damage. It is therefore not surprising that considerable energy and research is spent in trying to produce drugs which are more specific in their action and which would have less toxicity. So far this effort has gone largely unrewarded. The use of MCA's may represent an alternative strategy whereby the selective action of drugs may be increased for therapeutic benefit. Table 9.1 summarizes the potential of MCA's in clinical oncology.

Let us consider the use of adriamycin in the treatment of breast cancer. The drug belongs to a group of anti-cancer agents known as anthracycline antibiotics, and was originally isolated from a mutant strain of Streptomyces peucetius in the mid-1960s. Adriamycin has shown itself to be one of the most consistently effective drugs in the treatment of solid tumours when used alone or in combination with other drugs. However, it is associated with certain hazards immediately after administration to patients. They feel nauseated and frequently vomit, and develop complete loss of hair. This symptom alone can be psychologically very distressing for a patient already suffering from malignant disease. More importantly it has been shown to have a specific action on the muscle of the heart (myocardium) and for this reason it is necessary to constantly monitor the patients with electrocardiograms during adriamycin treatment and to limit the total dose to around 1000 mg in any individual patient. Beyond this dose acute heart failure and sudden death may occur. These distressing effects combine to limit the dose that can be given. When used alone in breast cancer, objective regression occurs in 40% of patients and it is not unreasonable to hope that if the dose and frequency of this drug delivered to the tumour could be increased then this response rate may also be improved. If an antibody were raised which could recognize breast tissue, then such an antibody when injected into a patient would localize to the tumour and/or normal breast tissue. If, prior to the injection of a breast-seeking antibody, adriamycin were to be conjugated chemically to the antibody in such a way that the antibody retained all its immunoreactivity, then it is possible that the antibody could act as a vehicle for targeting the drug onto the required tissue. This may have the effect of producing a high concentration of active drug within breast tissue while leaving little or no drug present in the general systemic circulation.

The advantages of such a delivery system can instantly be seen. Firstly it may be possible to produce, within the tumour, higher concentrations of active drug than are possible at present by intravenous injection, thus making the efficacy of the drug greater. Secondly, by reducing the circulating adriamycin to minute levels, much of the toxicity presently encountered may be avoided. This would make the drug safer to give, as well as being more acceptable to the patient. Methods for conjugating drugs onto antibodies have also been developed with considerable success. One remaining difficulty, however, is the uncoupling of the drug from the antibody when it reaches the target site. This step is necessary because most antitumour antibodies are directed against cell surface antigens. On the other hand, most anti-cancer drugs such as adriamycin need to gain entry into the cell itself. Therefore a major hurdle is to devise a method by which the active drug will become disassociated from its carrier antibody when the latter reaches its target on the cancer cell surface.